Magnesium-Promoted Additions of Difluoroenolates to Unactivated Imines

Article abstract of DOI:10.1021/acs.joc.7b03014

Although there are many synthetic methods to produce fluorinated and trifluoromethylated organic structures, the construction of difluoromethylated compounds remains a synthetic challenge. We have discovered that unactivated imines will react with difluoroenolates under exceedingly mild conditions when using magnesium salts and organic bases. We have applied this approach to the iminoaldol reaction to produce difluoromethylene groups as α,α-difluoro-β-amino-carbonyl groups. This method provides synthetically useful quantities of difficult to access α,α-difluoro-β-aminoketones without the need of protecting groups or the use of activated imines. Moreover, we have applied this strategy to create analogues of the dual orexin receptor antagonist, almorexant, in only two synthetic steps.

Full text of DOI:10.1021/acs.joc.7b03014

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Article
Magnesium-promoted Additions of Difluoroenolates to Unactivated Imines
Alex L. Nguyen, Hari Raj Khatri, James Ryan Woods, Cassidy
Shae Baldwin, Frank R Fronczek, and David A. Colby
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03014 • Publication Date (Web): 15 Feb 2018
Downloaded from http://pubs.acs.org on February 16, 2018
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The Journal of Organic Chemistry
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Magnesium-promoted Additions of Difluoroenolates to Unactivated
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Alex L. Nguyen,†,# Hari R. Khatri,†,# James R. Woods,‡ Cassidy S. Baldwin,† Frank R. Fronczek,§
and David A. Colby*,†
† Department of BioMolecular Sciences, University of Mississippi, University, Mississippi 38677, United States
‡ Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana,
47907, United States
§ Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803, United States
ABSTRACT: Although there are many synthetic methods to produce fluorinated and trifluoromethylated organic struc-
tures, the construction of difluoromethylated compounds remains a synthetic challenge. We have discovered that using
magnesium salts and organic bases, unactivated imines will react with difluoroenolates, generated under exceedingly mild
conditions. We have applied this approach to the iminoaldol reaction to produce difluoromethylene groups as α,α-difluoro-
β-amino-carbonyl groups. This method provides synthetically useful quantities of difficult to access α,α-difluoro-β-amino-
ketones without the need of protecting groups or the use of activated imines. Moreover, we have applied this strategy to
create analogues of the dual orexin receptor antagonist, almorexant, in only two synthetic steps.
OH
O
INTRODUCTION
Organic compounds displaying fluorine are particularly
HO
O
H
O
t-BuO
NH
F
O
valuable in the pharmaceutical, chemical, and agrochemi-
cal industries, because the presence of fluorine on a mole-
cule can drastically improve its chemical and biological
properties.1–3 Specifically in drug development, nearly 25%
of all marketed drugs contain at least one fluorine atom.4–
6 Numerous efforts for the synthesis of fluorine-containing
organic compounds have been reported, yet it is challeng-
ing to create some complex fluorinated structures.7,8 For
example, there are vastly more methods for the synthesis
of molecules displaying a trifluoromethyl group or a single
fluorine than a difluoromethylene group. A primary reason
is the difluoromethyl group is not a terminal group; and
therefore, newer strategies such as late-stage fluorination
cannot be readily applied. A uniquely appealing type of
difluorinated compound is a difluoro-β-amino acid, and the
typical synthetic target is an α,α-difluoro-β-amino-carbonyl
group. These building blocks have found potential use as
difluorinated drug leads9,10 and enzyme inhibitors (Figure
1).11–13
OAc
OBz
Ar
O
OH
F
O
O
H
F
docetaxel analogues
N
H
N
H
NH2
F
O
F
H
N
N
CH3(CH2)8
N
H
Boc Phe His
Ile Amp
O
O
F
H2N
rhodopeptin analogue
human plasma renin inhibitor
Ph
O
O
O
H
N
H
N
N
N
N
N
H
N
H
N
F
F
O
O
Ph
HIV-1 protease inhibitor
Figure 1. Examples of compounds displaying α,α-difluoro-β-
amino-carbonyl groups.
The synthesis of α,α-difluoro-β-amino-carbonyl groups
relies heavily on the addition of difluoroenolates to imines
that are activated with protecting groups on nitrogen. Alt-
hough the protecting groups assist in enhancing the reac-
tivity (i.e., electrophilicity) of the imine, the utility of pro-
tecting groups continues to decline as two protec-
tion/deprotection steps must be added into the overall
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synthetic plan. The addition of difluoroenolates to unpro-
such as N-sulfonyl,35,36 N-tosyl,36 N-Boc,35 and N-sulfinyl
imines,37 using the originally reported conditions of
LiBr/Et3N.25 These reactions provide the β-amino-α,α-
difluoroketones, bearing the corresponding N-substituent,
in high yields. Additional studies on the fragmentation of
highly α-fluorinated gem-diols have described a novel pho-
toredox-mediated addition to iminiums derived in situ
from tetrahydroquinolines;38 however, a general method to
add difluoroenolates produced from highly α-fluorinated
gem-diols to imines without the need of protecting/acti-
vating groups is not currently available.
1
2
3
4
5
6
7
8
tected, hence unactivated imines, is quite desirable but re-
mains synthetically challenging. Currently, there are only
two strategies to unite a difluoroenolate with an unacti-
vated imine: 1) Reformatsky additions of bromodifluoro-
ethyl acetate14–19 and bromodifluormethyl ketones20,21 2)
Mukaiyama additions of difluoroenoxy silanes (Figure 2).
Typically, Reformatsky reactions with bromodifluoroethyl
acetate are vigorous and therefore provide the cyclized lac-
tam.14,15 A diastereoselective variants have been reported,16–
9
18
and an indium-promoted version of the Reformatsky
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process has been developed to favor the amino-adduct ra-
ther than the lactam.19 This chemistry has been extended
to bromodifluoromethyl ketones in which the unactivated
imines react in the presence of copper and zinc.20,21 Unfor-
tunately, all of these reactions are restricted to a few esters
or ketones that bear the requisite bromodifluoromethyl
group. The traditional Mukaiyama addition of difluo-
roenoxysilanes to unactivated imines is limited to a single
example in the literature,22 because these imines easily hy-
drolyze under typical reaction conditions.23 Although the
addition of the Ruppert-Prakash reagent (i.e., CF3SiMe3) to
acyl silanes followed by treatment of nucleophilic fluorine
can generate reactive difluoroenoxysilanes in situ that add
to unactivated imines,24 more effective methods are clearly
needed. In order to address these deficiencies, we have de-
vised a method that unleashes difluoroenolates under mild
conditions yet tunes the reactivity to the unactivated
imine. Moreover, we have applied this strategy to produce
an α,α-difluoro-β-amino-carbonyl analogue of a drug can-
didate in only two synthetic steps.
Existing scope
O
OH
R2
trifluoroacetate
release
O
O
HO OH
R1
R2
R1
H
CF3
F
F
F
F
CF3CO2
O
H2O or
D2O
O
O
X
R1
X
R1
F
CF2H(D)
R1
F
F
SO2R3
O
N
X = Cl, Br, I
F
R2
R2
CF3
R2
H
O
CO2R3
H
HO CF3
R2
S
O
F
SO2R3
R2
S
R2
N
O
HN
F
R1
R2
F
F
R1
CO2R3
S
F
R1
R2
O
HN
F
F
R1
R2
activated imines
F
This work
R3
R2
R3
R2
O
HO OH
CF3
HN
F
N
O
MgI2, Et3N
+
R1
R1
H
F
F
F
unactivated imines
Figure 3. Preparation of α,α-difluoro-β-aminocarbonyl groups
from highly α-fluorinated gem-diols.
1) Reformatsky Additions
R1
R1
O
Herein, we describe a simple and mild method to add
difluoroenolates, produced from the release of trifluoro-
acetate from highly α-fluorinated gem-diols, to unacti-
vated imines. This task is accomplished by using magne-
sium salts and base. Also, we have applied this methodol-
ogy to synthesizing derivatives of tetrahydroisoquinolines,
and particularly, we have produced an α,α-difluoro-β-
amino-carbonyl derivative of the drug candidate, al-
morexant, using these iminoaldol reactions.
Et2Zn, RhCl(PPh3)3
ref. 12–13
N
N
BrCF2CO2Et
+
R2
F
H
R2
F
R
1,2 = aryl, alkyl
Ph
Ph
Ph
N
O
HN
In0
BrCF2CO2Et
O
+
EtO
ref. 15
H
Ph
R4
F
F
R4
Ph
O
HN
F
N
Zn, CuCl or CuBr
ref. 16–17
Br
+
R3
R3
H
Ph
F
F
F
R3 = aryl, CH2CO2Et
R
4 = aryl, Bn
RESULTS AND DISCUSSION
2) Mukaiyama Imino-aldols
PMP
OSiMe3
N
PMP
O
HN
Our initial studies began by examining the scope of re-
activity of the fluorinated gem-diol 125 with activated
imines using the reported conditions of LiBr/Et3N (Table
1).35–37 Imines 2–4 displaying an N-Boc,35 N-tosyl,36 or N-sul-
fonyl35,36 substituent participated in yields similar to the re-
ported values. Moreover, the oxaziridine 5 also is a suitable
electrophile for this process and provides the same product
9 as direct addition to the N-sulfonylimine 4. This type of
addition to an oxaziridine has not been reported from a
fluorinated gem-diol, to our knowledge. Also, the diazodi-
carboxylate 6 reacts with the difluoroenolate in the pres-
ence of LiBr and Et3N to produce hydrazine 10. This reac-
tivity with azodicarboxylates has been recently reported
using difluoroenoxysilanes as the difluoroenolate source,39
but it is not known in the literature from highly α-fluori-
nated gem-diols. Although these iminoaldol-type reactions
chiral acid
F
+
Ph
Ph
Ph
ref. 18
H
Ph
N
F
F
F
R6
R6
1. CF3SiMe3,
R6
R6
Bu4N+Ph3SnF2
–
O
HN
F
O
+
R5
2. BF3·OEt2
SiMe3
R5
H
F
ref. 20
R5 = Ph, C8H17
R6 = aryl, alkyl
Figure 2. Two existing methods to prepare α,α-difluoro-β-
amino-carbonyl groups from unactivated imines.
In 2011, we reported a mild approach for the generation
of difluoroenolates from highly α-fluorinated gem-diols
following the release of trifluoroacetate (Figure 3).25 These
difluoroenolates subsequently react with aldehydes,25,26
halogenation reagents,27,28 trifluoromethyl ketones,29 and
disulfides30 and can be quenched with water31 or D2O.32
This approach has been expanded to monofluoroeno-
lates.33,34 The difluoroenolates also add to activated imines,
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O
O
HN
F
Ph
demonstrate and expand the existing scope for the case of
LiBr/Et3N using activated imines, additional reactivity can
be easily tuned by selecting different reagents.
HO OH
CF3
N
Ph
additive, Et3N
+
1
2
3
4
5
6
7
8
Ph
H
Ph
THF, temp, 5 min
F
F
F
1
11
12
Yieldb
Table 1. LiBr/Et3N Promoted Additions of Difluoroenolates
Derived from Highly α-Fluorinated gem-Diols.
Imine (equiv.)
1.2
Entry
1
Additive
LiBr
Temp
rt
0%
0%
R
O
HO OH
O
HN
F
LiBr, Et3N
THF
CF3
+
2–6
R
Ph
LiCl
rt
2
3
1.2
1.2
1.2
1.2
2.0
2.0
2.0
2.0
2.0
F
F
F
1
7–10
MgBr2
50%a
60 °C
Yielda
Entry
1
Reactant
Product
9
MgCl2
MgI2
MgI2
MgI2
MgI2
60 °C
rt
74%a
43%
62%
66%
4
Boc
Boc
Ts
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
N
O
HN
88%
84%
87%
57%
91%
5
H
H
F
F
2
3
7
rt
6
Ts
N
O
HN
2
3
4
5
40 °C
60 °C
60 °C
rt
7
F
F
Cl
Cl
8
73% (95%)a
8
SO2Ph
SO2Ph
SO2Ph
N
N
O
HN
i-PrNMgCl·LiClc
i-PrMgCl·LiBrc
9
4%
H
F
F
4
5
6
10
54%
9
O
H
Yields determined by 19F NMR using trifluorotoluene as the
9
a
internal standard. b Isolated yields. c Et3N was not added.
CO2i-Pr
CO2i-Pr
CO2i-Pr
N
N
O
HN
We have previously reported the preparation of many
highly α-fluorinated gem-diols 1, 13–17.25,27,28 The scope of the
magnesium-promoted additions of unactivated imine 11 and
difluoroenolates derived from these highly α-fluorinated gem-
diols was characterized and is displayed in Table 3. A substan-
tial range of isolated yields (15–85%) of the β-amino-α,α-
difluoro ketones 12, 18–22 was observed. Typically, aromatic
groups (1, 13, 15, and 16) were fully compatible with the imino-
aldol process mediated by the release of trifluoroacetate and
isolated yields were 49–85%; however, alkyl substrates 14 and
17 provided the lowest yields of 15% and 25%, respectively.
This disparity demonstrates the scope of process when varying
only the α-fluorinated gem-diol.
N
i-PrO2C
F
F
10
a
Yields determined by 19F NMR using trifluorotoluene as the
internal standard.
The addition of the fluorinated gem-diol 125 and N-benzyli-
denebenzylamine 11 in the presence of Et3N and LiBr or LiCl
failed to provide any of the desired product 12 (Table 2, entries
1–2). This lack of reactivity using lithium salts and unactivated
imines has been previously reported.35 We hypothesized that
these entries (i.e., 1–2, Table 2) and the results in Table 1 were
due to the fact that lithium salts activate the lone pairs of elec-
trons associated with oxygen atoms whereas magnesium salts
activate lone pairs of electrons on nitrogen. Indeed, the ad-
vantages of magnesium salts have been demonstrated in sim-
ilar carbon-carbon bond forming process.40,41 Accordingly, ex-
changing lithium salts with MgBr2, MgCl2, and MgI2 (i.e., en-
tries 3–5, respectively) enabled addition to the unactivated
imine 11 and production of the desired adduct 12 in 43–74%
yields. Further optimizations revealed that 60 °C was the op-
timal temperature in the presence of MgI2 and product 12 was
produced in 95% yield as determined by 19F NMR. Isopropyl
magnesium chloride also provided the product 12 (entry 10),
as Grignard reagents are a functional class of bases for gener-
ating fluorinated nucleophiles.42
Table 3. Magnesium-promoted Addition of Highly α-Fluori-
nated gem-Diols to the Unactivated Imine 11a
O
HO OH
CF3
O
HN
Ph
N
Ph
MgI2, Et3N
+
R
R
Ph
H
Ph
THF, 60 °C, 5 min
F
F
F
F
11
1, 13-17
12, 18-22
Entry
1
Substrate
Product
Yieldb
73%
O
O
HN
Ph
HO OH
CF3
Ph
F
F
F
F
12
1
O
O
HN
Ph
HO OH
85%
15%
69%
49%
25%
CF3
Ph
2
3
4
5
6
F
F
F
F
13
18
Cl
Cl
O
O
HN
Ph
HO OH
CF3
Table 2. Optimization of Imino-aldol Process
Ph
F
F
F
F
14
19
O
O
HN
Ph
HO OH
CF3
Ph
F
F
F
F
S
S
20
15
O
O
HN
Ph
Ph
HO OH
O
O
O
O
CF3
Ph
F
F
F
F
21
16
O
O
HN
HO OH
CF3
Ph
F
F
F
F
22
17
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a Reactions were typically performed with MgI2 (4.2 equiv.) and
Et3N (2.1 equiv.), see Supporting Information for details. b Isolated
yields.
a Reactions were typically performed with MgI2 (4.2 equiv.) and
Et3N (2.1 equiv.), see Supporting Information for details. b Isolated
yields.
1
2
3
4
5
6
7
8
9
Next, the scope of reactivity of unactivated imines 23–29
with the gem-diol 1 was investigated using the magnesium-
promoted aldol reaction (Table 4). The effects of both of the
substituents on the imine were examined by varying alkyl
groups as well as aryl groups with electron-donating and elec-
tron-withdrawing substituents. Flame-dried magnesium io-
dide was needed to obtain good yields in some examples.40 In
the case of imine 23, with a phenyl groups at each substituent,
the product 30 was obtained in 59% isolated yield. The pres-
ence of an electron-donating methoxy group on phenyl imine
24 enabled a higher yield of 79% whereas the presence of an
electron-withdrawing fluorine on the phenyl imine 32 resulted
in a similar yield of 64%. On the hand, the methoxylphenyl
imine 26 bearing a N-fluorophenyl substituent gave a high
yield of 78%, yet the bis-methoxylphenyl imine 27 resulted in
a lower 38% yield. Imines bearing a N-t-butyl group (28, entry
6) or N-benzyl group (29, entry 7) produced yields of 30 and
61%, respectively. This method provides quick access to useful
quantities of compounds bearing α,α-difluoro-β-amino-car-
bonyl groups, and thus, X-ray structures of 30, 31, and 32
were obtained.
The trifluoroacetate-release mediated imino aldol reaction
using unactivated imines has substantial potential in the cre-
ation of α,α-difluoro-β-amino-carbonyl groups on organic
molecules. A previous report demonstrated the utility of the
trifluoroacetate-release aldol reaction in adding difluoroeno-
lates to iminiums derived in situ from N-substituted tetrahy-
droisoquinoline using visible light-induced photoredox catal-
ysis.38 We envisioned that the magnesium-initiated process
could be analogously applied to dihydroisoquinolines to pro-
vide tetrahydroisoquinolines. Using this approach, the gem-
diol 1 was added to dihydroisoquinoline 37 in the presence of
MgI2 and Et3N to provide the corresponding tetrahydroiso-
quinoline α,α-difluoro ketones 38 in good 84% yield (Scheme
1). Suzuki–Miyaura cross-coupling of 38 with vinyltrifluorobo-
rate43 provided the tetrahydroisoquinoline 39 in 40% yield and
demonstrates structural variants of tetrahydroquinolines can
be quickly created.
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. Imino-aldol addition of gem-diol 1 with dihydroi-
soquinoline 37
Br
Br
Table 4. Magnesium-promoted Addition of Highly α-Fluori-
nated gem-Diol 1 to the Unactivated Imines 23–29a
BF3K
N
O
PdCl2, PPh3
37
N
H
1
Cs2CO3
THF/H2O (9:1)
40%
MgI2, Et3N
THF, 60 °C
84%
R1
R2
F
38
F
R1
R2
O
O
HN
HO OH
CF3
N
MgI2, Et3N
+
H
THF, 60 °C, 5 min
F
F
F
F
23-29
30-36
1
O
Entry
1
Product
Yieldb
Imine
N
H
F
F
39
X-ray
O
HN
N
59%
79%
H
H
F
F
23
Tetrahydroisoquinolines are a valuable class of heterocycle
that appears in bioactive natural products, such as the ectein-
ascidins,44 as well as drug discovery (Figure 4).45 Notably, al-
morexant belongs to a class of drugs that act as dual orexin
receptor antagonist for treatment of sleep disorders and dis-
plays a key tetrahydroisoquinoline.46 There are few reported
enantioselective syntheses of almorexant that involved key
steps such as asymmetric transfer hydrogenation,47 asymmet-
ric allylic amidation,48 and asymmetric induction with N-tert-
butanesulfinamide.49 In addition, several almorexant ana-
logues have been synthesized and reported.50
30
X-ray
X-ray
O
HN
N
2
3
4
5
6
7
F
F
24
OMe
OMe
31
O
HN
N
N
64%
78%
38%
30%
61%
H
F
F
25
F
F
F
F
32
O
HN
OMe
HO
H
MeO
F
F
NH
S
OMe
OMe
OMe
26
OMe
OMe
33
MeO
HO
Me
O
AcO
O
H
N
Me
N
N
O
HN
NMe
O
Ph
N
F3C
H
O
F
F
HN
OMe
OMe
27
28
29
OH
O
34
almorexant
ecteinascidin 743
O
HN
Figure 4. Structure of biologically active molecules displaying
a tetrahydroisoquinoline.
H
F
F
35
We envisioned a strategy to produce derivatives of al-
morexant using the magnesium-promoted reaction between a
fluorinated gem-diol and a dihydroquinoline (Scheme 2). Fur-
thermore, this approach would be short and not require any
protecting groups. Accordingly, the known fluorinated gem-
diol 4038 and 6,7-dimethoxy-3,4-dihydroisoquinoline 41 were
O
HN
Ph
N
Ph
H
F
F
36
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21.4; 19F NMR (282 MHz, CDCl3) –103.87 (dd, JFF = 284.0, JHF
=
treated with MgI2 and Et3N and gave the α,α-difluoro-β-ami-
1
2
3
4
5
6
7
8
11.8 Hz, 1F), –105.92 (dd, JFF = 284.2, JHF = 12.6 Hz, 1F); IR (film)
νmax 3584, 3234, 3055, 2974, 2920, 1702 cm–1; HRMS (ESI) m/z
calcd for C26H20O3NSClF2Na (M+Na)+ 522.0718, found
522.0721.
noketone 42. Next, 42 was coupled using the literature
method48 to amide 4350 to give a 2.2:1 mixture of diastere-
omers and the major isomer was purified in 28% isolated
yield. Accessing the almorexant derivative 44 in two syn-
thetic steps is a functional demonstration of this method
and displays how the unique α,α-difluoro-β-amino-car-
bonyl group integrates into known bioactive structures.
N-(2,2-Difluoro-3-(naphthalen-2-yl)-3-oxo-1-phe-
nylpropyl)benzenesulfonamide 9.51 To
a solution of
2,2,4,4,4-pentafluoro-3,3-dihydroxy-1-(naphthalene-2-yl)bu-
tan-1-one 125,27 (30 mg, 0.09 mmol) and N-benzylideneben-
zenesulfonamide 4 (28 mg, 0.11 mmol) in THF (620 μL) was
added LiBr (24 mg, 0.28 mmol), and the mixture was stirred
for 10 min at rt. Next, Et3N (26 μl, 0.19 mmol) was added drop-
wise, and after 5 min, the reaction mixture was quenched with
saturated aqueous NH4Cl (3 mL). The resultant mixture was
extracted with EtOAc (2 mL × 3). The organics were dried over
Na2SO4 and concentrated under reduced pressure. SiO2 flash
chromatography (2:1:1 hexane/Et2O/CHCl3) afforded the title
compound 9 as a colorless solid in 87 % yield (37 mg): mp 132–
135 °C; 1H NMR (300 MHz, CDCl3) δ 8.46 (s, 1H), 7.92 (d, J = 8.0
Hz, 1H), 7.88–7.82 (m, 3H), 7.71–7.61 (m, 3H), 7.57 (t, J = 7.4
Hz, 1H), 7.41 (t, J = 7.1 Hz, 1H), 7.31–7.18 (m, 7H), 5.73 (m, 1H),
5.32 (td, J = 12.2, 9.9 Hz, 1H); 13C NMR (125 MHz CDCl3) 188.6
(t, JCF = 29.0 Hz, 1C), 140.1, 136.0, 132.7 (t, JCF = 4.3 Hz, 1C), 132.5,
132.4, 132.1, 130.1, 129.6, 129.3, 128.8, 128.7 (2C), 128.6, 128.5 (2C),
128.4 (2C), 127.7, 127.1, 126.9 (2C), 124.4, 116.3 (t, JCF = 261.9 Hz,
1C), 60.2 (t, JCF = 25.0 Hz, 1C); 19F NMR (282 MHz, CDCl3) δ
−103.77 (dd, JFF = 280, JHF = 12.0 Hz, 1F), –105.48 (dd, JFF = 280,
JHF = 12.8 Hz, 1F); IR (film) νmax 3272, 1696, 1331, 1284, 1166 cm–
1; HRMS (ESI-TOF) m/z calcd for C25H19F2NO3SNa [M+Na]+
474.0951, found 474.0962.
Scheme 2. Two-step, protecting group-free synthesis of fluor-
inated almorexant analogue 44.
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
OMe
MeO
MeO
MeO
O
N
O
HO OH
CF3
41
N
H
F
F
MgI2, Et3N
THF, 60 °C
34%
F
F
F3C
F3C
40
42
OMe
OTs
MeO
O
H
N
O
43
N
i-Pr2NEt, CH3CN
28% (dr = 2.2:1)
F
F
Ph
O
F3C
HN
44
CONCLUSIONS
In summary, we have reported a new protocol to synthesize
β-amino-α,α-difluoro ketones using magnesium-promoted
additions of difluoroenolates with unactivated imines. The
difluoroenolates were unleashed from highly α-fluorinated
gem-diols using only MgI2 and Et3N following the release of
trifluoroacetate. This process eliminates the need of an imine
with an activating N-substituent or a protecting group. This
approach is compatible with many alkyl and aryl substituted
imines and gem-diols. It can be easily integrated into drug dis-
covery, and we have demonstrated its potential use in the syn-
thesis of the analogues of almorexant in only two steps. These
reactions further establish the role of releasing trifluoroace-
tate in the presence of mild reagents, such as a salt and an or-
ganic base, to generate valuable and reactive difluoroenolates.
N-(2,2-Difluoro-3-(naphthalen-2-yl)-3-oxo-1-phe-
nylpropyl)benzenesulfonamide 9. 2,2,4,4,4-Pentafluoro-
3,3-dihydroxy-1-(naphthalen-2-yl)butan-1-one 125,27 (8 mg,
0.02 mmol) was azeotroped with toluene (3 × 1 mL) and dis-
solved in THF (0.3 mL). Next, the solution was added to a flask
containing LiBr (8.0 mg, 0.92 mmol) and cooled to –78 °C un-
der an argon atmosphere. A solution of Davis oxaziridine D1
(14 mg, 0.054 mmol), that was azeotroped with toluene (3 × 1
mL) and dissolved in THF (0.20 mL), was added dropwise to
the reaction mixture and stirred for 15 min at –78 °C. Next,
Et3N (5 µL, 0.04 mmol) was added, and the resultant mixture
was allowed to warm slowly to rt and stirred for 24 h at rt.
Then, the reaction mixture was quenched with saturated
NH4Cl solution (5 mL), extracted with EtOAc (3 × 10 mL),
washed with brine (3 × 5 mL), and dried over Na2SO4. The or-
ganics were concentrated under reduced pressure and puri-
fied by preparative TLC using 30% EtOAc in hexanes to give
the title compound 9 as a colorless solid (6 mg, 57%).
EXPERIMENTIAL SECTION
N-(1-(4-Chlorophenyl)-2,2-difluoro-3-(naphthalen-2-
yl)-3-oxopropyl)-4-methylbenzene-sulfonamide 8.51 To a
solution of 2,2,4,4,4-pentafluoro-3,3-dihydroxy-1-(naphtha-
len-2-yl)butan-1-one 125,27 (65.7 mg, 0.205 mmol), N-(4-chloro-
benzylidene)-4-methylbenzenesulfonamide 3 (133 mg, 0.452
mmol) and LiBr (101 mg, 1.16 mmol) in THF (3 mL) was added
was Et3N (60 µL, 0.43 mmol) dropwise. After 5 min, the reac-
tion was quenched with saturated aqueous NH4Cl (5 mL), and
the resultant mixture was extracted with EtOAc (5 mL × 5).
The organics were dried over Na2SO4 and concentrated under
reduced pressure. SiO2 flash column chromatography (9:1–8:2
hexanes/EtOAc) afforded the title compound 8 as a yellow
solid in 84% yield (86.1 mg): mp 143–145 °C; 1H NMR (300 MHz,
CDCl3) 8.47 (s, 1H), 8.00–7.82 (m, 4H), 7.72–7.50 (m, 4H), 7.19
(s, 4H), 7.09 (d, J = 8.1 Hz, 2H), 5.66 (d, J = 9.5 Hz, 1H), 5.26
(td, J = 12.2, 9.5 Hz, 1H), 2.32 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 188.3 (t, JCF = 29.1 Hz, 1C), 143.7, 136.9, 136.1, 134.9, 132.8, 132.1,
130.1, 130.0 (3C), 129.7, 129.4 (2C), 129.0, 128.6 (3C), 127.8, 127.0
(3C), 124.4, 116.1 (t, JCF = 262.1 Hz, 1C), 59.6 (t, JCF = 25.4 Hz, 1C),
Diisopropyl
1-(1,1-difluoro-2-(naphthalen-2-yl)-2-ox-
oethyl)hydrazine-1,2-dicarboxylate 10. To a solution of
2,2,4,4,4-pentafluoro-3,3-dihydroxy-1-(naphthalen-2-yl)bu-
tan-1-one 125,27 (30 mg, 0.094 mmol) and LiBr (35 mg, 0.40
mmol) in THF (0.8 mL) at rt was added diisopropyl azodicar-
boxylate (40 µL, 0.20 mmol) followed by Et3N (28 µL, 0.20
mmol). The reaction mixture was warmed to 60 °C for 30 min.
Then, the reaction mixture was cooled to rt, quenched with 1
mL of saturated NH4Cl solution (5 mL), extracted with EtOAc
(3 × 10 mL), washed with brine (3 × 5 mL), dried over Na2SO4,
and concentrated under reduced pressure. Purification by
SiO2 flash chromatography using 5–10% EtOAc in hexanes
provided the title compound 10 as a colorless oil (35 mg, 91 %):
1H NMR (500 MHz, CDCl3) δ 9.17 (s, 1H), 8.27 (d, J = 8.0 Hz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 10
1H), 8.09 (d, J = 7.2 Hz, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.86 (d, J
TOF) m/z calcd for C22H19ClF2NO (M+H)+ 386.1123, found
386.1131.
1-(Benzylamino)-2,2-difluoro-5-methyl-1-phenylhexan-
1
2
3
4
5
6
7
8
= 8.1 Hz, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H),
6.88 (s, 1H), 5.13 (qu, J = 6.2 Hz, 1H), 4.82 (t, J = 5.6 Hz, 1H),
1.34 (d, J = 4.6 Hz, 6H), 1.11 (d, J = 6.0 Hz, 6H); 13C NMR (125
MHz, CDCl3) δ 181.8 (t, JCF = 29.4 Hz, 1C), 155.5, 152.1, 135.8,
132.7, 132.4, 130.3, 129.1, 129.0, 128.4, 127.6, 126.8, 124.5, 112.7 (t,
JCF = 259.6 Hz, 1C), 73.4, 70.8, 21.9, 21.8, 21.3, 21.2; 19F NMR (470
MHz, CDCl3) δ –86.96 (d, JFF= 190.5 Hz, 2F); IR νmax 3319, 2984,
2934, 1736, 1717, 1628, 1428, 1376, 1249, 1104, 1045 cm–1; HRMS
(ESI-TOF) m/z calcd for C20H21F2N2O5 [M–H]– 407.1419, found
407.1418.
3-one 19. See representative reaction procedure. To a solution
of 1,1,1,3,3-pentafluoro-2,2-dihydroxy-6-methylheptan-4-one
1425 (32.6 mg, 0.130 mmol) and N-benzylidinebenzylamine 11
(51 µL, 0.27 mmol) in THF (1.0 mL) was added MgI2 (152 mg,
0.547 mmol) and the mixture was stirred for 2 min at rt. The
resultant mixture was warmed to 60 °C for 1 min and then Et3N
(38 µL, 0.27 mmol) was added. SiO2 flash chromatography
(100% hexanes–5:5:0.01 hexanes/EtOAc/Et3N) afforded the ti-
tle compound 19 as a colorless oil (6.3 mg) in 15% yield: 1H
NMR (400 MHz, CDCl3) δ 7.43–7.38 (m, 3H), 7.35 (d, J = 7.6
Hz, 2H), 7.32–7.25 (m, 3H), 7.19 (d, J = 6.9 Hz, 2H), 4.22 (dd, J
= 20.6, 7.6 Hz, 1H), 3.73 (d, J = 13.0 Hz, 1H), 3.52 (d, J = 13.0 Hz,
1H), 2.52 (dd, J = 18.1, 6.9 Hz, 1H), 2.39 (dd, J = 18.1, 6.4 Hz, 1H),
2.16 (septet, J = 6.6 Hz, 1H), 1.68 (br s, 1H), 0.93 (d, J = 6.7 Hz,
3H), 0.89 (d, J = 6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 201.5
(dd, JCF = 31.1, 26.5 Hz, 1C), 139.0, 134.4, 128.9 (2C), 128.7, 128.6
(2C), 128.4 (2C), 128.3 (2C), 127.3, 116.4 (dd, JCF = 260.0, 256.6
Hz, 1C), 62.8 (dd, JCF = 26.4, 21.6 Hz, 1C), 51.0, 46.7, 23.4, 22.4
(2C); 19F NMR (376 MHz, CDCl3) δ ‒109.9 (dd, JFF = 258.6, JHF
= 7.5 Hz, 1F), ‒123.6 (dd, JFF = 258.8, JHF = 20.5 Hz, 1F); IR (film)
νmax 2959, 1740, 1455, 1124 cm–1; HRMS (ESI-TOF) m/z calcd for
C20H24F2NO (M+H)+ 332.1826, found 332.1828.
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
Representative Reaction Procedure for Trifluoroace-
tate Release/Imino-Aldol Reaction. To a solution of
2,2,4,4,4-pentafluoro-3,3-dihydroxy-1-(naphthalene-2-yl)bu-
tan-1-one 125,27 (50 mg, 0.16 mmol) and N-benzylidinebenzyla-
mine 11 (62 µL, 0.33 mmol) in THF (1.0 mL) was added MgI2
(182 mg, 0.656 mmol). The resultant mixture was stirred for 2
min at rt. Then, the mixture was warmed to 60 °C for 1 min
and then Et3N (46 µL, 0.33 mmol) was added. After 5 min of
stirring at 60 °C, the reaction was quenched with saturated
aqueous NH4Cl (1.5 mL) and the resultant mixture was ex-
tracted with EtOAc (10 mL × 3). The organics were dried over
Na2SO4 and concentrated under reduced pressure. The mix-
ture was then treated with saturated NaHSO3 solution (15 mL)
and stirred vigorously for 18 h. Next, the mixture was extracted
with EtOAc (10 mL × 3). The organics were dried over Na2SO4
and concentrated under reduced pressure. SiO2 flash chroma-
tography (9:1:0.01 hexanes/EtOAc/Et3N) afforded the product
12 as a colorless solid in 73% yield (45.8 mg).
1-(Benzo[b]thiophen-3-yl)-3-(benzylamino)-2,2-
difluoro-3-phenylpropan-1-one 20. See representative reac-
tion procedure. To a solution of 1-(benzo[b]thiophen-3-yl)-
2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 1527 (31 mg,
0.10 mmol) and N-benzylidinebenzylamine 11 (38 µL, 0.20
mmol) in THF (570 µL) was added MgI2 (112 mg, 0.402 mmol)
and the mixture was stirred for 2 min at rt. The resultant mix-
ture was warmed to 60 °C for 1 min and then Et3N (28 µL, 0.20
mmol) was added. SiO2 flash chromatography (9:1:0.01 hex-
anes/EtOAc/Et3N) afforded the title compound 20 as a pale
3-(Benzylamino)-2,2-difluoro-1-(naphthalen-2-yl)-3-
phenylpropan-1-one 12.51 See representative reaction proce-
dure: mp 96–98 °C; 1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H),
8.00 (d, J = 8.7 Hz, 1H), 7.91–7.86 (m, 3H), 7.64 (m, 1H), 7.56
(m, 1H), 7.46‒7.36 (m, 5H), 7.09‒7.03 (m, 5H), 4.48 (dd, J =
20.1, 7.7 Hz, 1H), 3.76 (d, J = 13.1 Hz, 1H), 3.49 (d, J = 13.1 Hz,
1H), 1.82 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 190.3 (t, JCF
=
1
yellow solid (26.7 mg) in 69% yield: mp 106–108 °C; H NMR
28.4 Hz, 1C), 138.6, 135.7, 134.4, 132.2, 132.1, 130.4, 130.0, 129.1
(2C), 129.0, 128.7, 128.6 (2C), 128.4, 128.2 (4C), 127.7, 127.0, 126.8,
124.8, 118.1 (t, JCF= 258.5 Hz, 1C), 63.8 (t, JCF = 24.3 Hz, 1C), 50.9;
19F NMR (282 MHz, CDCl3) δ –102.7 (dd, JFF = 268.4, JHF = 7.6
Hz, 1F), –115.3 (dd, JFF = 268.4, JHF = 20.1 Hz, 1F); IR (film) νmax
1701, 1626, 1455, 1114, 698 cm–1; HRMS (EI-BE) m/z calcd for
C26H22F2NO (M+H)+ 402.1669, found 402.1664.
(400 MHz, CDCl3) δ 8.73 (d, J = 8.2 Hz, 1H), 8.40 (s, 1H), 7.90
(d, J = 8.0 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz,
1H), 7.44–7.35 (m, 5H), 7.16–6.99 (m, 5H), 4.43 (dd, J = 19.8, 8.0
Hz, 1H), 3.78 (d, J = 13.2 Hz, 1H), 3.51 (d, J = 13.2 Hz, 1H), 2.02
(br s, 1H); 13C NMR (125 MHz, CDCl3) δ 184.7 (dd, JCF = 29.0,
27.9 Hz, 1C), 140.0 (t, JCF = 9.0 Hz, 1C), 138.9, 138.7, 137.2, 134.5,
129.8, 129.1 (2C), 128.7, 128.6 (2C), 128.1 (4C), 127.1, 126.1, 125.7,
125.3, 122.1, 117.7 (dd, JCF = 260.4, 256.8 Hz, 1C), 63.7 (dd, JCF
=
3-(Benzylamino)-1-(4-chlorophenyl)-2,2-difluoro-3-
phenylpropan-1-one 18.51 See representative reaction proce-
dure. To a solution of 1-(4-chlorophenyl)-2,2,4,4,4-pen-
tafluoro-3,3-dihydroxybutan-1-one 1325,27 (30.9 mg, 0.101
mmol) and N-benzylidinebenzylamine 11 (38 µL, 0.20 mmol)
in THF (680 µL) was added MgI2 (112 mg, 0.404 mmol). The
mixture was warmed to 60 °C for 1 min and then Et3N (30 µL,
0.20 mmol) was added. SiO2 flash chromatography (9:1:0.01
hexanes/EtOAc/Et3N) afforded the title compound 18 as a col-
orless oil (33.1 mg) in 85% yield: 1H NMR (300 MHz, CDCl3) δ
7.91 (d, J = 8.4 Hz, 2H), 7.47‒7.36 (m, 7H), 7.22‒7.17 (m, 3H),
7.10‒7.04 (m, 2H), 4.38 (dd, J = 20.7, 7.2 Hz, 1H), 3.77 (d, J = 13.1
Hz, 1H), 3.49 (d, J = 13.1 Hz, 1H), 2.11 (br s, 1H); 13C NMR (125
MHz, CDCl3) δ 189.3 (t, JCF = 27.5 Hz, 1C), 140.4, 138.5, 134.2,
131.6 (2C), 131.1, 129.0 (2C), 128.9 (2C), 128.8, 128.6 (2C), 128.3
26.2, 22.0 Hz, 1C), 50.7; 19F NMR (376 MHz, CDCl3) δ –103.8
(dd, JFF = 263.0, JHF = 7.5 Hz, 1F), –116.1 (dd, JFF = 263.0, JHF
=
18.8 Hz, 1F); IR (film) νmax 1675, 1458, 1106, 698 cm–1; HRMS
(ESI-TOF) m/z calcd for C24H20F2NOS (M+H)+ 408.1234, found
408.1235.
1-(Benzo[d][1,3]dioxol-5-yl)-3-(benzylamino)-2,2-
difluoro-3-phenylpropan-1-one 21.51 See representative re-
action procedure. To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-
2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 1625 (16 mg,
0.05 mmol) and N-benzylidinebenzylamine 11 (20 µL, 0.105
mmol) in THF (800 µL) was added MgI2 (57 mg, 0.205 mmol)
and the mixture was stirred for 2 min at rt. The resultant mix-
ture was warmed to 60 °C for 5 min and then Et3N (14 µL, 0.10
mmol) was added. Preparative TLC (8:2 hexanes/EtOAc) af-
forded the desired product 21 as a colorless solid (12 mg) in
61% yield: mp 89–91 °C; 1H NMR (500 MHz, CDCl3) δ 7.63 (d, J
= 8.3 Hz, 1H), 7.45 (s, 1H), 7.40 (m, 5H), 7.24–7.19 (m, 3H), 7.14–
7.09 (m, 2H), 6.82 (d, J = 8.3 Hz, 1H), 6.07 (dd, J = 5.7, 1.3 Hz,
(2C), 128.2 (2C), 127.2, 117.8 (t, JCF = 255.0 Hz, 1C), 63.4 (t, JCF
=
22.5 Hz, 1C), 50.8; 19F NMR (282 MHz, CDCl3) δ ‒102.8 (dd, JFF
= 268.7, JHF = 6.5 Hz, 1F), ‒116.4 (dd, JFF = 268.5, JHF = 18.6 Hz,
1F); IR (film) νmax 1693, 1444, 1266, 1039, 699 cm–1; HRMS (ESI-
ACS Paragon Plus Environment

Page 7 of 10
The Journal of Organic Chemistry
2H), 4.39 (dd, J = 20.0, 7.6 Hz, 1H), 3.77 (d, J = 13.2 Hz, 1H), 3.50
mmol) and N-(4-methoxybenzylidene)aniline 24 (44 mg, 0.21
(d, J = 13.2 Hz, 1H), 2.18 (br s, 1H); 13C NMR (125 MHz, CDCl3)
δ 188.1 (t, JCF = 28.8 Hz, 1C), 152.5, 148.0, 138.8, 134.5, 129.1 (2C),
128.6, 128.5 (2C), 128.2 (4C), 127.5, 127.1, 126.7, 117.8 (t, JCF = 258.4
Hz, 1C), 109.5, 108.0, 102.0, 63.7 (t, JCF = 23.7 Hz, 1C), 50.8; 19F
NMR (470 MHz, CDCl3) δ ‒102.5 (dd, JFF = 269.1, JHF = 7.3 Hz,
1F), ‒114.53 (dd, JFF = 269.1, 20.0 Hz, 1F); IR (film) νmax 1693,
1444, 1265, 1039, 699 cm–1; HRMS (ESI-TOF) m/z calcd for
C23H20F2NO3 (M+H)+ 396.1411, found 396.1405.
mmol) in THF (1.0 mL) was added MgI2 (115 mg, 0.414 mmol)
and the mixture was stirred for 2 min at rt. The resultant mix-
ture was warmed to 60 °C for 1 min and then Et3N (29 µL, 0.21
mmol) was added. SiO2 flash chromatography (9:1:0.01 hex-
anes/EtOAc/Et3N) afforded the title compound 31 as a dark
orange solid (32.5 mg) in 79% yield. Recrystallization from a
solution of hexanes and CH2Cl2 (by slow evaporation) pro-
vided a crystalline solid suitable for X-ray structure analysis:
mp 126–128 °C; 1H NMR (500 MHz, CDCl3) δ 8.52 (s, 1H), 7.98
(d, J = 8.7 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 5.7 Hz,
1H), 7.87 (d, J = 5.1 Hz, 1H), 7.64 (t, J = 7.4 Hz, 1H), 7.57 (t, J =
7.2 Hz, 1H), 7.41 (d, J = 8.5 Hz, 2H), 7.11 (t, J = 7.9 Hz, 2H), 6.88
(d, J = 8.7 Hz, 2H), 6.72 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 7.9 Hz,
2H), 5.34 (dt, J = 16.3, 8.0 Hz, 1H), 4.58 (d, J = 7.3 Hz, 1H), 3.76
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 189.9 (dd, JCF = 29.2, 28.1
Hz, 1C), 159.8, 145.6, 135.8, 132.4 (t, JCF = 4.5 Hz, 1C), 132.1, 130.1,
130.0, 129.7 (2C), 129.3, 129.2 (2C), 128.5, 127.7, 127.0, 126.3, 124.6,
118.8, 117.5 (t, JCF = 259.8 Hz, 1C), 114.2 (2C), 114.1 (2C), 60.0 (dd,
JCF = 25.7, 22.9 Hz, 1C), 55.2; 19F NMR (470 MHz, CDCl3) δ ‒
104.2 (dd, JFF = 270.4, JHF = 9.1 Hz, 1F), ‒112.1 (dd, JFF = 270.4, JHF
= 16.6 Hz, 1F); IR (film) νmax 1694, 1626, 1465, 1106, 692 cm–1;
HRMS (ESI-TOF) m/z calcd for C26H22F2NO2 (M+H)+ 418.1619,
found 418.1613.
1
2
3
4
5
6
7
8
1-(Adamantan-1-yl)-3-(benzylamino)-2,2-difluoro-3-
phenylpropan-1-one 22. See representative reaction proce-
dure. To a solution of 1-(adamantan-1-yl)-2,2,4,4,4-pen-
tafluoro-3,3-dihydroxybutan-1-one 1725,27 (35 mg, 0.11 mmol)
and N-benzylidinebenzylamine 11 (42 µL, 0.23 mmol) in THF
(570 µL) was added MgI2 (126 mg, 0.452 mmol) and the mix-
ture was stirred for 2 min at rt. The resultant mixture was
warmed to 60 °C for 1 min and then Et3N (31 µL, 0.23 mmol)
was added. SiO2 flash chromatography (100% hexanes–5:5:0.01
hexanes/CH2Cl2/Et3N) afforded the title compound 22 as a col-
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
1
orless solid (10.8 mg) in 25% yield: mp 104–106 °C; H NMR
(400 MHz, CDCl3) δ 7.43–7.16 (m, 10H), 4.39 (dd, J = 20.2, 8.4
Hz, 1H), 3.72 (d, J = 13.0 Hz, 1H), 3.54 (d, J = 13.0 Hz, 1H), 2.02
(s, 3H), 1.88 (q, J = 12.4 Hz, 6H), 1.79 (br s, 1H), 1.71 (q, J = 12.0
Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 204.6 (dd, JCF = 28.4, 25.3
Hz, 1C), 139.3, 134.8, 129.1, 128.4 (4C), 128.3 (2C), 128.2 (2C),
127.1, 118.7 (dd, JCF = 264.1, 259.9 Hz, 1C), 62.9 (dd, JCF = 25.4,
21.1 Hz, 1C), 51.1, 46.5, 36.9 (3C), 36.4 (3C), 27.7 (3C); 19F NMR
(376 MHz, CDCl3) δ –103.8 (dd, JFF = 270.7, JHF = 7.5 Hz, 1F), –
116.9 (dd, JFF = 268.8, JHF = 20.7 Hz, 1F); IR (film) νmax 2907,
2852, 1716, 1454, 1114 cm–1; HRMS (ESI-TOF) m/z calcd for
C26H30F2NO (M+H)+ 410.2295, found 410.2279.
3-((3,4-Dimethylphenyl)amino)-2,2-difluoro-3-(4-
fluorophenyl)-1-(naphthalen-2-yl)propan-1-one 32. See
representative reaction procedure. To a solution of 2,2,4,4,4-
pentafluoro-3,3-dihydroxy-1-(naphthalene-2-yl)butan-1-one
125,27 (29 mg, 0.09 mmol), 4Å molecular sieves (100 mg), and
3,4-dimethyl-N-(4-fluorobenzylidene)aniline 25 (44 mg, 0.19
mmol) in THF (1.7 mL) was added flame-dried MgI2 (107 mg,
0.385 mmol) and the mixture was stirred for 2 min at rt. The
resultant mixture was warmed to 60 °C for 1 min and then Et3N
(25 µL, 0.19 mmol) was added. The crude mixture was recrys-
tallized from chloroform and hexanes to afford the title com-
pound 32 as a pale yellow solid (25 mg) in 64% yield. Recrys-
tallization from a solution of hexanes and CH2Cl2 (by slow
evaporation) provided a crystalline solid suitable for X-ray
structure analysis: mp 141–143 °C; 1H NMR (500 MHz, CDCl3) δ
8.54 (s, 1H), 7.96 (dd, J = 15.4, 8.6 Hz, 2H), 7.88 (t, J = 7.3 Hz,
2H), 7.65 (t, J = 7.4 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.45 (t, J =
6.1 Hz, 2H), 7.04 (t, J = 8.6 Hz, 2H), 6.84 (d, J = 8.1 Hz, 1H), 6.41
(s, 1H), 6.32 (d, J = 8.1 Hz, 1H), 5.32 (dt, J = 17.7, 7.3 Hz, 1H), 4.36
(d, J = 7.7 Hz, 1H), 2.10 (s, 3H), 2.08 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 189.6 (dd, JCF = 29.3, 27.7 Hz, 1C), 162.8 (d, JCF = 247.5
Hz, 1C), 143.3, 137.4, 135.9, 132.3 (t, JCF = 4.5 Hz, 1C), 132.2, 130.5
(d, JCF = 2.5 Hz, 1C), 130.2, 130.2 (d, JCF = 8.0 Hz, 2C), 130.1, 130.0,
129.4, 128.6, 127.7, 127.2, 127.0, 124.6, 117.4 (t, JCF = 248.5 Hz, 1C),
116.1, 115.6 (d, JCF = 21.6 Hz, 2C), 111.5, 60.1 (dd, JCF = 26.0, 22.7
Hz, 1C), 19.9, 18.6; 19F NMR (470 MHz, CDCl3) δ ‒103.0 (dd, JFF
= 272.9, 1F), ‒113.3 (dd, JFF = 272.2, JHF = 15.7 Hz, 1F), ‒114.4 (s,
1F); IR (film) νmax 1692, 1507, 1212, 1063 cm–1; HRMS (ESI-TOF)
m/z calcd for C27H23F3NO (M+H)+ 434.1732, found 434.1725.
2,2-Difluoro-1-(naphthalen-2-yl)-3-phenyl-3-(phenyla-
mino)propan-1-one 30. See representative reaction proce-
dure. To a solution of 2,2,4,4,4-pentafluoro-3,3-dihydroxy-1-
(naphthalene-2-yl)butan-1-one 125,27 (24 mg, 0.075 mmol), 4Å
molecular sieves (100 mg), and N-benzylideneaniline 23 (27
mg, 0.15 mmol) in THF (1.5 mL) was added flame-dried MgI2
(84 mg, 0.302 mmol), and the mixture was stirred for 2 min at
rt. The resultant mixture was warmed to 60 °C for 1 min and
then Et3N (21 µL, 0.15 mmol) was added. The crude mixture
was recrystallized from chloroform and hexanes to afford the
title compound 30 as a yellow solid (17 mg) in 59% yield. Re-
crystallization from a solution of hexanes and CH2Cl2 (by slow
evaporation) provided a crystalline solid suitable for X-ray
1
structure analysis: mp 149–151 °C; H NMR (400 MHz, CDCl3)
δ 8.50 (s, 1H), 7.98–7.83 (m, 4H), 7.64 (t, J = 7.5 Hz, 1H), 7.57
(t, J = 7.5 Hz, 1H), 7.48 (d, J = 7.3 Hz, 2H), 7.38–7.28 (m, 3H),
7.10 (t, J = 7.9 Hz, 2H), 6.71 (t, J = 7.3 Hz, 1H), 6.62 (d, J = 7.8
Hz, 2H), 5.38 (dt, J = 17.4, 8.9 Hz, 1H), 4.60 (d, J = 8.9 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 189.9 (dd, JCF = 29.5, 27.9 Hz, 1C),
145.5, 135.8, 134.5, 132.4 (dd, JCF = 5.0, 4.4 Hz, 1C), 132.2, 130.1,
130.0, 129.3, 129.2 (2C), 128.7, 128.7 (2C), 128.6 (2C), 128.5, 127.7,
127.0, 124.6, 118.9, 117.5 (dd, JCF = 260.8, 259.3 Hz, 1C), 114.2 (2C),
60.6 (dd, JCF = 25.7, 22.6 Hz); 19F NMR (376 MHz, CDCl3) δ ‒
103.6 (dd, JFF = 272.0, JHF = 8.8 Hz, 1F), ‒112.2 (dd, JFF = 272.1, JHF
= 17.1 Hz, 1F); IR (film) νmax 1694, 1455, 1285, 1105 cm–1; HRMS
(ESI-TOF) m/z calcd for C25H20F2NO (M+H)+ 388.1513, found
388.1506.
2,2-Difluoro-3-((4-fluorophenyl)amino)-3-(4-methoxy-
phenyl)-1-(naphthalen-2-yl)propan-1-one 33. See repre-
sentative reaction procedure. To a solution of 2,2,4,4,4-pen-
tafluoro-3,3-dihydroxy-1-(naphthalene-2-yl)butan-1-one 125,27
(32 mg, 0.10 mmol) and N-(4-methoxybenzylidene)-4-
fluoroaniline 26 (48 mg, 0.21 mmol) in THF (570 µL) was
added MgI2 (115 mg, 0.414 mmol) and the mixture was stirred
for 2 min at rt. The resultant mixture was warmed to 60 °C for
1 min and then Et3N (29 µL, 0.21 mmol) was added. SiO2 flash
2,2-Difluoro-3-(4-methoxyphenyl)-1-(naphthalen-2-yl)-
3-(phenylamino)propan-1-one 31. See representative reac-
tion procedure. To a solution of 2,2,4,4,4-pentafluoro-3,3-di-
hydroxy-1-(naphthalene-2-yl)butan-1-one 125,27 (32 mg, 0.10
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The Journal of Organic Chemistry
Page 8 of 10
chromatography (9:1:0.01 hexanes/EtOAc/Et3N) afforded the
CDCl3) δ ‒100.9 (dd, JFF = 258.8, JHF = 6.4 Hz, 1F), ‒117.5 (dd, JFF
1
2
3
4
5
6
7
8
title compound 33 as a dark orange oil (33.5 mg) in 78% yield:
1H NMR (500 MHz, CDCl3) δ 8.50 (s, 1H), 7.97 (d, J = 8.7 Hz,
1H), 7.92 (d, J = 8.1 Hz, 1H), 7.89–7.81 (m, 2H), 7.64 (t, J = 7.5
Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.37 (d, J = 7.8 Hz, 2H), 6.87 (d,
J = 7.7 Hz, 2H), 6.80 (t, J = 8.7 Hz, 2H), 6.55 (m, 2H), 5.23 (dt,
J = 17.0, 8.5 Hz, 1H), 4.44 (d, J = 8.6 Hz, 1H), 3.76 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 189.9 (t, JCF = 28.9 Hz, 1C), 159.9,
156.5 (d, JCF = 236.9 Hz, 1C), 141.9 (d, JCF = 1.9 Hz, 1C), 135.8,
132.4 (dd, JCF = 5.2, 4.3 Hz, 1C), 132.2, 132.0, 130.1, 130.0, 129.7
(2C), 128.5, 127.7, 127.0, 126.1, 124.6, 117.5 (t, JCF = 259.9 Hz, 1C),
115.7 (d, JCF = 22.5 Hz, 2C), 115.3 (d, JCF = 7.5 Hz, 2C), 114.1 (2C),
61.0 (dd, JCF = 25.9, 22.8 Hz, 1C), 55.2; 19F NMR (376 MHz,
CDCl3) δ ‒103.9 (dd, JFF = 271.8, JHF = 8.6 Hz, 1F), ‒112.4 (dd, JFF
= 271.8, JHF = 16.9 Hz, 1F), ‒127.1 (sept, J = 3.8 Hz, 1F); IR (film)
νmax 1692, 1626, 1114 cm–1; HRMS (ESI-TOF) m/z calcd for
C26H21F3NO2 (M+H)+ 436.1524, found 436.1515.
= 258.8, JHF = 22.2 Hz, 1F); IR (film) νmax 1698, 1456, 1108, 1077
cm–1; HRMS (ESI-TOF) m/z calcd for C23H24F2NO (M+H)+
368.1826, found 368.1825.
(4E,6E)-3-(Benzylamino)-2,2-difluoro-1-(naphthalen-2-
yl)octa-4,6-dien-1-one 36. See representative reaction proce-
dure. To a solution of 2,2,4,4,4-pentafluoro-3,3-dihydroxy-1-
(naphthalene-2-yl)butan-1-one 125,27 (20 mg, 0.06 mmol) and
N-(hexa-2,4-dien-1-ylidene)-1-phenylmethanamine 29 (30 mg,
0.16 mmol, 5:1 (2E,4E)-isomer/(2E,4Z)-isomer mixture*) in
THF (1 mL) was added flame-dried MgI2 (56 mg, 0.20 mmol)
and the mixture was stirred for 2 min at rt. The resultant mix-
ture was warmed to 60 °C for 1 min and then Et3N (14 µL, 0.10
mmol) was added. SiO2 flash chromatography (9:1:0.01 hex-
anes/Et2O/Et3N) afforded the title compound 36 as a yellow
oil in 61% yield (12 mg, 5:1 mixture of isomers*): 1H NMR (500
MHz, CDCl3) δ 8.57* (s, 1H), 8.55 (s, 1H), 8.03 (dd, J = 8.7, 1.4
Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.65
(td, J = 7.5, 1.1 Hz, 1H), 7.57 (td, J = 7.5, 1.2 Hz, 1H), 7.13–7.03 (m,
5H), 6.56* (dd, J = 15.2, 11.0 Hz, 1H), 6.24 (dd, J = 15.1, 10.4 Hz,
1H), 6.15 (qd, J = 12.5, 1.3 Hz, 1H), 5.79 (dq, J = 13.2, 6.6 Hz, 1H),
5.54 (dd, J = 14.7, 8.8 Hz, 1H), 3.86 (d, J = 13.4 Hz, 1H), 3.83 (m,
1H), 3.60 (d, J = 13.2 Hz, 1H), 1.80 (d, J = 6.6 Hz, 3H), 1.61 (br s,
1H); 13C NMR (125 MHz, CDCl3) δ 190.1 (t, JCF = 28.2 Hz, 1C),
138.9, 136.8, 135.7, 132.2, 132.0, 131.5, 130.5, 130.0, 129.1, 128.4, 128.1
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
2,2-Difluoro-3-(4-methoxyphenyl)-3-((4-methoxy-
phenyl)amino)-1-(naphthalen-2-yl)propan-1-one 34. See
representative reaction procedure. To a solution of 2,2,4,4,4-
pentafluoro-3,3-dihydroxy-1-(naphthalene-2-yl)butan-1-one
125,27 (35 mg, 0.11 mmol) and N-(4-methoxybenzylidene)-4-
methoxyaniline 27 (55 mg, 0.23 mmol) in THF (570 µL) was
added magnesium iodide (127 mg, 0.455 mmol) and the mix-
ture was stirred for 2 min at rt. The resultant mixture was
warmed to 60 °C for 1 min and then Et3N (32 µL, 0.23 mmol)
was added. SiO2 flash chromatography (8:2:0.01 hex-
anes/EtOAc/Et3N) afforded the title compound 34 as a dark
orange oil (12.3 mg) in 25% yield: 1H NMR (500 MHz, CDCl3) δ
8.51 (s, 1H), 7.98 (d, J = 8.7 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.88
(dd, J = 8.2, 5.5 Hz, 2H), 7.64 (t, J = 7.5 Hz, 1H), 7.57 (t, J = 7.5
Hz, 1H), 7.37 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.67
(d, J = 9.0 Hz, 2H), 6.55 (d, J = 8.9 Hz, 2H), 5.21 (dd, J = 17.6,
8.6 Hz, 1H), 4.25 (d, J = 9.0 Hz, 1H), 3.76 (s, 3H), 3.67 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 190.0 (dd, JCF = 29.5, 27.7 Hz, 1C),
159.8, 153.0, 139.5, 135.8, 132.3 (dd, JCF = 5.3, 3.9 Hz, 1C), 132.2,
130.3, 130.0, 129.7 (2C), 129.3, 128.5, 127.7, 127.0, 126.5, 124.7, 117.7
(dd, JCF = 260.8, 258.2 Hz, 1C), 115.9 (2C), 114.7 (2C), 114.1 (2C),
61.2 (dd, JCF = 26.0, 22.4 Hz, 1C), 55.6, 55.2; 19F NMR (470 MHz,
CDCl3) δ ‒103.6 (dd, JFF = 270.1, JHF = 8.5 Hz, 1F), ‒113.3 (dd, JFF
= 270.0, JHF = 17.6 Hz, 1F); IR (film) νmax 1693, 1509, 1114 cm–1;
HRMS (ESI-TOF) m/z calcd for C27H24F2NO3 (M+H)+ 448.1724,
found 448.1721.
(2C), 128.1 (2C), 127.7, 126.9, 126.8, 124.8, 123.0, 118.1 (t, JCF
=
257.4 Hz, 1C), 62.2 (dd, JCF = 26.3, 22.4 Hz, 1C), 50.5, 18.2, 13.6;
19F NMR (470 MHz, CDCl3) δ ‒103.2 (dd, JFF = 268.9, JHF = 7.5
Hz, 1F), ‒115.5 (dd, JFF = 268.9, JHF = 18.8 Hz, 1F); IR (film) νmax
1700, 1454, 1116, 990, 699 cm–1; HRMS (ESI-TOF) m/z calcd for
C25H24F2NO (M+H)+ 392.1826, found 392.1841. * denotes minor
isomer.
2-(5-Bromo-1,2,3,4-tetrahydroisoquinolin-1-yl)-2,2-
difluoro-1-(naphthalen-2-yl)ethenone 38. See representa-
tive reaction procedure. To a solution of 2,2,4,4,4-pentafluoro-
3,3-dihydroxy-1-(naphthalene-2-yl)butan-1-one 125,27 (92.6 mg,
0.289 mmol) and 5-bromo-3,4-dihydroisoquinoline 37 (127
mg, 0.605 mmol) in THF (1.7 mL) was added MgI2 (340 mg,
1.22 mmol) and the mixture was stirred for 5 min at rt. The
resultant mixture was warmed to 60 °C for 5 min and then
Et3N (85 µL, 0.61 mmol) was added. SiO2 flash chromatog-
raphy (5:5:0.01 hexanes/CH2Cl2/Et3N) afforded the title com-
pound 38 as a pale yellow solid (101.7 mg) in 84% yield: mp 112–
114 °C; 1H NMR (500 MHz, CDCl3) δ 8.63 (s, 1H), 8.07 (d, J = 8.7
Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.89
(d, J = 8.2 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.58 (d, J = 7.9 Hz,
1H), 7.55 (d, J = 7.7 Hz, 1H), 7.41 (dd, J = 7.7, 2.7 Hz, 1H), 7.11 (t,
J = 7.9 Hz, 1H), 4.89 (dd, J = 21.0, 8.2 Hz, 1H), 3.26 (m, 1H), 3.02
(m, 1H), 2.85–2.66 (m, 2H), 1.89 (br s, 1H); 13C NMR (100 MHz,
CDCl3) δ 190.6 (dd, JCF = 29.8, 27.8 Hz, 1C), 136.8, 135.8, 132.2 (t,
3-(tert-Butylamino)-2,2-difluoro-1-(naphthalen-2-yl)-3-
phenylpropan-1-one 35. See representative reaction proce-
dure. To a solution of 2,2,4,4,4-pentafluoro-3,3-dihydroxy-1-
(naphthalene-2-yl)butan-1-one 125,27 (32 mg, 0.10 mmol) and
N-benzylidene-tert-butylamine 28 (37 µL, 0.21 mmol) in THF
(570 µL) was added MgI2 (115 mg, 0.414 mmol) and the mixture
was stirred for 2 min at rt. The resultant mixture was warmed
to 60 °C for1 min and then Et3N (29 µL, 0.21 mmol) was added.
SiO2 flash chromatography (9:1:0.01 hexanes/EtOAc/Et3N) af-
forded the title compound 35 as a colorless solid (10.7 mg) in
J
CF = 8.3 Hz, 1C), 132.1, 131.9, 130.6, 130.0, 129.2, 128.5, 127.7 (2C),
127.6, 126.9 (2C), 125.7, 124.8, 118.9 (dd, JCF = 265.1, 258.5 Hz,
1C), 57.1 (t, JCF = 23.4 Hz, 1C), 39.5, 29.6; 19F NMR (376 MHz,
CDCl3) δ ‒96.0 (dd, JFF = 270.5, JHF = 7.2 Hz, 1F), ‒110.4 (dd, JFF
= 270.5, JHF = 21.0 Hz, 1F); IR (film) νmax 1698, 1440, 1173, 754 cm-
1; HRMS (ESI-TOF) m/z calcd for C21H17BrF2NO (M+H)+
416.0462, found 416.0448.
1
30% yield: mp 106–108 °C; H NMR (400 MHz, CDCl3) δ 8.59
(s, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.94–
7.84 (m, 2H), 7.63 (t, J = 7.5 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H),
7.45–7.43 (m, 2H), 7.41–7.29 (m, 3H), 4.63 (dd, J = 22.0, 6.5 Hz,
1H), 1.83 (br s, 1H), 0.84 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
192.0 (dd, JCF = 30.5, 26.5 Hz, 1C), 138.3, 135.6, 132.2, 132.0 (t, JCF
= 2.9 Hz, 1C), 131.9, 131.4, 129.9, 128.9, 128.7 (2C), 128.4 (2C),
128.2, 127.7, 126.8, 125.1, 118.3 (dd, JCF = 260.9, 257.3 Hz, 1C), 59.5
(dd, JCF = 26.9, 21.2 Hz, 1C), 51.5, 30.0 (3C); 19F NMR (376 MHz,
2,2-Difluoro-1-(naphthalen-2-yl)-2-(5-vinyl-1,2,3,4-tet-
rahydroisoquinolin-1-yl)ethan-1-one 39. To a solution of 2-
(5-bromo-1,2,3,4-tetrahydroisoquinolin-1-yl)-2,2-difluoro-1-
(naphthalen-2-yl)ethenone 38 (23.5 mg, 0.056 mmol) in THF
(0.3 mL) and water (40 µL), PdCl2 (4.1 mg, 0.023 mmol), PPh3
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The Journal of Organic Chemistry
(5.8 mg, 0.02 mmol), Cs2CO3 (67.6 mg, 0.207 mmol), and po-
aqueous Na2CO3 (5 mL) and extracted with EtOAc (5 mL). The
1
2
3
4
5
6
7
8
tassium vinyltrifluoroborate (9.7 mg, 0.07 mmol) were added,
and the resultant mixture was allowed to stir for 23 h at 85 °C
in a sealed tube. The reaction mixture was warmed to rt,
quenched with water (2 mL), and extracted with CH2Cl2 (2
mL). The aqueous layer was extracted with CH2Cl2 (2 mL × 3).
The organics were dried over Na2SO4 and concentrated under
reduced pressure. SiO2 flash chromatography (100:0.01
CH2Cl2/Et3N) afforded the title compound 39 as a pale yellow
oil (8.3 mg) in 40% yield: 1H NMR (500 MHz, CDCl3) δ 8.61 (s,
1H), 8.08 (d, J = 8.6 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.91 (d, J =
8.8 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.63 (t, J = 7.4 Hz, 1H), 7.56
(t, J = 7.5 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 7.2 Hz,
1H), 7.23 (t, J = 7.6 Hz, 1H), 6.90 (dd, J = 17.3, 11.0 Hz, 1H), 5.62
(d, J = 17.3 Hz, 1H), 5.32 (d, J = 10.9 Hz, 1H), 4.93 (dd, J = 20.6,
8.3 Hz, 1H), 3.26 (m, 1H), 3.00 (m, 1H), 2.79–2.70 (m, 2H), 1.89
(br s, 1H); 13C NMR (100 MHz, CDCl3) δ 190.9 (dd, JCF = 29.7,
27.7 Hz, 1C), 137.2, 135.7, 134.7, 134.1, 132.2, 132.1 (dd, JCF = 5.1, 4.0
Hz, 1C), 130.8, 130.0, 129.7, 129.1, 128.4, 128.2, 128.1, 127.7, 126.9,
125.7, 125.3, 124.9, 116.3 (dd, JCF = 264.6, 258.5 Hz, 1C), 57.4 (t,
JCF = 23.6 Hz, 1C), 39.6, 26.1; 19F NMR (376 MHz, CDCl3) δ ‒
96.6 (dd, JFF = 268.8, JHF = 5.6 Hz, 1F), ‒110.6 (dd, JFF = 268.8,
JHF = 20.5 Hz, 1F); IR (film) νmax 2923, 1698, 1627, 1466, 1074, 736
cm–1; HRMS (ESI-TOF) m/z calcd for C23H20F2NO (M+H)+
364.1513, found 364.1510.
organics were dried over Na2SO4 and concentrated under re-
duced pressure to give a 2.2:1 mixture of diastereomers. SiO2
flash chromatography (5:5:0.01 hexanes/EtOAc/Et3N) afforded
the title compound 44 as a colorless oil (4.6 mg, major isomer)
1
in 28% yield: H NMR (500 MHz, CDCl3) δ 8.11 (d, J = 8.2 Hz,
2H), 7.80 (d, J = 8.4 Hz, 2H), 7.02 (t, J = 7.7 Hz, 2H), 6.69 (s,
1H), 6.52 (m, 1H), 6.45 (d, J = 7.5 Hz, 2H), 6.37 (d, J = 2.4 Hz,
1H), 4.19 (s, 1H), 3.91 (s, 3H), 3.89 (m, 1H), 3.79 (s, 3H), 3.52 (m,
1H), 3.12 (m, 1H), 2.92 (dd, J = 14.8, 7.0 Hz, 1H), 2.79 (d, J = 4.9
Hz, 3H), 2.58 (dd, J = 17.4, 5.6 Hz, 1H), 2.18 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 189.3 (t, JCF = 27.5 Hz, 1C), 171.2, 149.5, 147.4,
135.6, 135.5 (d, JCF = 32.9 Hz, 1C), 134.8, 129.4 (dt, JCF = 2.6, 2.3
Hz, 2C), 129.1 (2C), 128.9, 128.6 (2C), 128.5, 127.8, 126.2 (dt, JCF
= 3.7, 3.6 Hz, 2C), 124.7 (t, JCF = 283.3 Hz, 1C), 118.3 (t, JCF = 263.3
Hz, 1C), 111.5, 111.1 (d, JCF = 3.3 Hz, 1C), 69.7, 60.5 (dd, JCF = 28.0,
23.1 Hz, 1C), 56.1, 55.8, 42.3, 29.7, 25.9; 19F NMR (376 MHz,
CDCl3) δ ‒64.3 (s, 3F), ‒95.4 (dd, JFF = 259.9, JHF = 10.2 Hz, 1F),
‒106.6 (dd, JFF = 259.5, JHF = 20.9 Hz, 1F); IR (film) νmax 2922,
1712, 1664, 1466, 1116, 701 cm–1; HRMS (ESI-TOF) m/z calcd for
C29H28F5N2O4 (M+H)+ 563.1969, found 563.1968.
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ASSOCIATED CONTENT
Supporting Information.
Spectroscopic data from 1H, 13C and 19F NMR, and X-ray exper-
imental and data. The Supporting Information is available free
of charge on the ACS Publications website.
2-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-
2,2-difluoro-1-(4-(trifluoromethyl)-phenyl)ethan-1-one
42. See representative reaction procedure. To a solution of
2,2,4,4,4-pentafluoro-3,3-dihydroxy-1-(4-(trifluorome-
thyl)phenyl)butan-1-one 4038 (117 mg, 0.345 mmol) and 6,7-di-
methoxy-3,4-dihydroisoquinoline 41 (139 mg, 0.728 mmol) in
THF (2.5 mL) was added MgI2 (469.5 mg, 1.688 mmol) and the
mixture was stirred for 5 min at rt. The resultant mixture was
warmed to 60 °C for 5 min and then Et3N (101 µL, 0.723 mmol)
was added. SiO2 flash chromatography (5:5:0.01 hex-
anes/EtOAc/Et3N) afforded the title compound 42 as a pale
AUTHOR INFORMATION
Corresponding Author
* dacolby@olemiss.edu
Present Addresses
1
yellow solid (49.2 mg) in 34% yield: mp 128–130 °C; H NMR
James R. Woods: Alkermes, Inc., Waltham, Massachusetts
02451, United States
Alex L. Nguyen: Louisiana State University, Alexandria, Loui-
siana, 71302, United States
(400 MHz, CDCl3) δ 8.12 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.3 Hz,
2H), 6.88 (d, J = 2.4 Hz, 1H), 6.62 (s, 1H), 4.74 (dd, J = 21.2, 7.6
Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.12 (m, 1H), 2.95 (dt, J = 3.2,
1.3 Hz, 1H), 2.63 (dt, J = 1.1, 1.0 Hz, 2H), 1.62 (br s, 1H); 13C NMR
(100 MHz, CDCl3) δ 191.2 (dd, JCF = 31.6, 27.8 Hz, 1C), 148.7,
147.2, 136.8, 134.6 (d, J = 32.9 Hz, 1C), 130.0 (td, JCF = 2.5, 1.2 Hz,
2C), 129.6, 125.4 (td, JCF = 3.7, 3.6 Hz, 2C), 124.8 (t, JCF = 287.7
Hz, 1C), 120.7, 118.9 (dd, JCF = 264.7, 256.9 Hz, 1C), 111.7, 111.1 (d,
J = 5.6 Hz, 1C), 56.5 (t, JCF = 23.8 Hz, 1C), 56.0, 55.8, 39.8, 28.6;
Author Contributions
A.L.N., H.R.K., J.R.W., and C.S.B. conducted the synthetic ex-
periments and acquired analytical data. F.R.F. acquired the X-
ray data. D.A.C., A.L.N., and J.R.W. wrote the manuscript and
#
designed the experimental approach. The authors contrib-
uted equally to this work.
19F NMR (376 MHz, CDCl3) δ –64.4 (s, 3F), ‒97.2 (dd, JFF
=
265.9, JHF = 6.2 Hz, 1F), ‒113.3 (dd, JFF = 265.9, JHF = 21.1 Hz, 1F);
IR (film) νmax 2927, 1714, 1518, 1465, 1129, 732 cm–1; HRMS (ESI-
TOF) m/z calcd for C20H19F5NO3 (M+H)+ 416.1285, found
416.1281.
Funding Sources
Funding for this work is from the University of Mississippi and
the National Institute of General Medical Sciences (Grant
P20GM104932).
(2R)-2-(1-(1,1-Difluoro-2-oxo-2-(4-(trifluorome-
thyl)phenyl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquino-
lin-2(1H)-yl)-N-methyl-2-phenylacetamide 44. To a solu-
tion of 2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-
2,2-difluoro-1-(4-(trifluoromethyl)phenyl)ethan-1-one 42 (12.1
mg, 0.029 mmol) and (S)-2-(methylamino)-2-oxo-1-phe-
nylethyl 4-methylbenzenesulfonate 4348 (10.2 mg, 0.032
mmol) in CH3CN (1.0 mL) was added i-Pr2NEt (10 μL, 0.06
mmol). The resultant mixture was stirred for 26 h at 85 °C.
Then, reaction mixture was cooled to rt and concentrated un-
der reduced pressure. The mixture was washed with saturated
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
The authors acknowledge funding from the University of Mis-
sissippi and the National Institute of General Medical Sciences
(Grant P20GM104932). Its contents are solely the responsibil-
ity of the authors and do not necessarily represent the official
view of the National Institutes of Health (NIH). The Mass
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(23) Yuan, Z.; Wei, Y.; Shi, M. Tetrahedron 2010, 66, 7361–7366.
(24) Jonet, S.; Cherouvrier, F.; Brigaud, T.; Portella, C. Eur. J.
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Spectrometry and Proteomic Facility of the University of
Notre Dame and Mass Spectrometry Facility of the Louisiana
State University are acknowledged for acquisition of high-res-
olution mass spectrometry data.
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R3
R3
O
HO OH
CF3
O
HN
F
N
MgI2, Et3N
15 examples
+
R1
R1
R2
R2
H
THF, 60 °C, 5 min
F
F
F
unactivated
imines
R1, R2, R3 = aryl, alkyl
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