A new tandem cross metathesis-intramolecular aza-Michael reaction for the synthesis of α,α-difluorinated lactams

Article abstract of DOI:10.1055/s-0031-1290964

A new tandem cross metathesis-intramolecular aza-Michael reaction in which an α,α-difluorinated amide serves as a source of nucleophilic nitrogen is described. This process gives rise to a new family of fluorinated γ- and δ-lactams. The tandem protocol is catalyzed by the Hoveyda-Grubbs second-generation ruthenium catalyst with titanium(IV) tetraisopropoxide as a co-catalyst and it is highly efficient when conjugated ketones are used as the Michael acceptors. With conjugated esters, however, it is necessary to perform a step-by-step procedure in which the cyclization event is activated by the addition of a base. An asymmetric version of the process is also evaluated. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290964

SPECIAL TOPIC
▌1863
sApecNial etowpic Tandem Cross Metathesis–Intramolecular Aza-Michael Reaction for
the Synthesis of α,α-Difluorinated Lactams
Tandem Reaction for the Synthesis of α,α-Difluorinated Lactams
Santos Fustero,* Claribel Báez, María Sánchez-Roselló, Amparo Asensio, Javier Miro, Carlos del Pozo*
Departamento de Química Orgánica, Universidad de Valencia, 46100 Burjassot, Spain
Fax +34(96)3544939; E-mail: santos.fustero@uv.es; E-mail: carlos.pozo@uv.es
Received: 07.03.2012; Accepted: 13.03.2012
cross metathesis (CM) variant was initially underdevel-
Abstract: A new tandem cross metathesis–intramolecular aza-
oped because of a lack of predictability in the product dis-
Michael reaction in which an α,α-difluorinated amide serves as a
tribution and the stereoselectivity of the reaction.
However, the development of new ruthenium-based com-
source of nucleophilic nitrogen is described. This process gives rise
to a new family of fluorinated γ- and δ-lactams. The tandem proto-
col is catalyzed by the Hoveyda–Grubbs second-generation rutheni- plexes that exhibit improved efficiency and tolerance to
um catalyst with titanium(IV) tetraisopropoxide as a co-catalyst and
it is highly efficient when conjugated ketones are used as the Mi-
chael acceptors. With conjugated esters, however, it is necessary to
perform a step-by-step procedure in which the cyclization event is
various functional groups changed the situation and it is
now possible to achieve perfect control of E/Z selectivity
in CM reactions.6
activated by the addition of a base. An asymmetric version of the
process is also evaluated.
Y
HN
Y
O
O
X
N
X
IMAMR
Key words: Michael additions, tandem reactions, catalysis, hetero-
cycles, fluorine, amides, asymmetric catalysis
R1
R1
( )n
( )n
X = CO, CH2
Y = alkyl, aryl, SO2Ar, SOAr, CO2R2
R1 = H, alkyl, aryl, OR2
Tandem processes usually generate high levels of molec-
ular complexity in a single chemical operation thereby
minimizing the use of solvents and reagents and reducing
the time and number of steps involved in purification.
These advantages make tandem transformations extreme-
ly appealing from both academic and industrial points of
view. Indeed, tandem protocols have been extensively de-
veloped in recent decades, and they have found a wide va-
riety of applications in natural-product synthesis.1
Moreover, asymmetric versions greatly enhance the use-
fulness and relevance of tandem reactions and these have
become extremely powerful and popular tools for synthet-
ic organic chemists.2
IMAMR = intramolecular aza-Michael reaction
nitrogen-containing
heterocycles
Scheme 1 Intramolecular aza-Michael reactions
In terms of their selectivities and yields, both aza-
Michael3c,7 and olefin metathesis reactions8 exhibit suit-
able properties for participation in effective tandem proto-
cols. In fact, each of these reactions has been combined
with other types of transformations in many tandem se-
quences. However, only a few examples of combinations
of CM and AMR have been reported, probably because of
the poor compatibility of ruthenium catalysts with the ba-
sic nitrogen-containing functionalities that are necessary
to effect the hetero-Michael addition. This difficulty can,
however, be overcome by the use of weak nucleophiles,
such as amides, carbamates, or nitrogen heterocycles, in
conjunction with Lewis acids as co-catalysts. For in-
stance, appropriately substituted pyrroles9 and indoles10
have been shown to be good partners in tandem CM–in-
tramolecular aza-Michael reaction (IMAMR) sequences.
Our previous studies have shown that carbamates11 or N-
sulfinyl amines12 as nitrogen sources in the presence of
boron trifluoride etherate or titanium(IV) tetraisopropox-
ide, respectively, can also participate in highly efficient
CM–IMAMR protocols.
The conjugated addition of nitrogen-centered nucleo-
philes to the β-carbon of electron-deficient olefins, the so-
called aza-Michael reaction (AMR), is a particularly inter-
esting transformation because it probably represents the
shortest route to β-amino carbonyl derivatives, such as β-
amino acids. Furthermore, a wide variety of nitrogen nu-
cleophiles and Michael acceptors can participate in this
process, which is also simple and displays significant
atom economy.3 The intramolecular version of the AMR
is especially relevant because it permits the direct genera-
tion of nitrogen-containing heterocycles, yielding natural
products and pharmaceutically relevant molecules in a
relatively simple manner (Scheme 1).4
Olefin metathesis is one of the most powerful methods for
the formation of carbon–carbon double bonds.5 In com-
parison with the ring-closing metathesis reaction, the
Among heterocyclic compounds, fluorinated lactams oc-
cupy a prominent position in organofluorine chemistry.
These are interesting cyclic systems that are present in a
SYNTHESIS 2012, 44, 1863–1873
Advanced online publication: 27.04.2012
DOI: 10.1055/s-0031-1290964; Art ID: SS-2012-C0238-ST
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

1864
S. Fustero et al.
SPECIAL TOPIC
wide range of natural and synthetic biologically active other hand, with conjugated ketones, which are better
molecules and drug candidates.13 In pursuit of our ongo- Michael acceptors than esters, as the reaction partners,
ing interest in the development of methods for the prepa- metathesis was followed by cyclization through IMAMR
ration of fluorine-containing heterocycles,14 we in a highly efficient manner to give the fluorinated lac-
hypothesized that it might be possible to perform a tan- tams in a single step. When amides 1 were subjected to the
dem CM–IMAMR protocol that would provide a route for conditions discussed above in the presence of methyl vi-
the synthesis of a new family of fluorinated γ- and δ-lac- nyl ketone (2b), a tandem reaction led to the desired prod-
tams 3 (Scheme 2). In this process, an α,α-difluorinated ucts 3 in moderate yields (Table 1, entries 7–10).
amide 1 would be employed as the source of a nitrogen
Table 1 Results for the Tandem CM–IMAMR Sequence
nucleophile. Here, we report our attempts to carry out this
synthetic sequence and to extend it in an asymmetric
form.
F
O
F
Mes
N
N Mes
Ru
( )n
Cl
R2
O
N
O
Cl
F
F
O
F
R1
O
R1
i-Pr
Ru-I (5 mol%)
O
O
O
F
( )n
R1
N
3
F
N
R2
F
H
+
R2
+
R2
( )n
H
+
O
N
( )n
co-catalyst (10 mol%)
2a (R2 = OEt)
2b (R2 = Me)
R1
R1
CH2Cl2, reflux
CM
O
NH
1
IMAMR
1
2
O
F
3
R2
R1 = PMP, OMe, SAMP
R
( )n
F
2 = Me, OEt, (–)-8-phenylmenthyl
5
Scheme 2 Synthetic strategy
Entry Reactants
Co-catalyst Time Product 3 Product 5
[yielda (%)] [yielda (%)]
(h)
First, we assembled a series of fluorinated amides 1 by
condensation of various primary amines with gem-difluo-
rinated carboxylic acids 4,15 via the corresponding acid
chlorides, to give difluoro amides 1 in moderate yields
(Scheme 3).
1
2
1a
1a
1b
1b
1c
1d
1a
1b
1c
1d
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
Ti(Oi-Pr)4
BF3·OEt2
Ti(Oi-Pr)4
BF3·OEt2
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
5
5
–
5a (90)
5a (80)
5b (71)
5b (76)
5c (89)
5d (75)
–
–
3
5
–
4
2
–
1. (COCl)2, CH2Cl2
DMF (cat.)
F
F
F
F
H
N
OH
5
5
–
R1
( )n
( )n
2. Et3N, R1NH2
DMAP (cat.)
O
O
6
6
–
1a (n = 1, R1 = PMP; 40%)
1b (n = 1, R1 = OMe; 44%)
1c (n = 2, R1 = PMP; 38%)
1d (n = 2, R1 = OMe; 60%)
4a (n = 1)
4b (n = 2)
7
8
3e (61)
3f (58)
3g (51)
3h (49)
8
10
8
–
9
–
Scheme 3 Preparation of starting fluorinated amides 1a–d
10
10
–
On the basis of our previous findings,11,12 we decided to
study the tandem process in the presence of a Lewis acid
to establish the feasibility of our new tandem CM–
IMAMR with fluorinated amides. The reaction of fluori-
nated amide 1a with ethyl acrylate (2a) in the presence of
the Hoveyda–Grubbs second-generation catalyst Ru-I
and titanium(IV) tetraisopropoxide as a co-catalyst in re-
fluxing dichloromethane gave the CM product 5a in ex-
cellent yield after five hours (Table 1, entry 1). Similar
results were obtained when boron trifluoride etherate was
used as the co-catalyst (Table 1, entry 2). Likewise, am-
ides 1b–d reacted under the same conditions to give good
yields of the corresponding CM products 5b–d (Table 1,
entries 3–6).
a Isolated yield after flash column chromatography.
Having prepared α,β-unsaturated esters 5 by the CM reac-
tion of amides 1 with ethyl acrylate (2a), we attempted to
perform the IMAMR under basic conditions, since the
conjugate addition of amides as Michael donors is often
activated by the presence of bases as catalysts. In this
manner, we hoped to obtain fluorinated lactams 3 corre-
sponding to cyclic derivatives of β-amino acids.
Amides 5a and 5c, each bearing a p-methoxyphenyl
(PMP) group on the nitrogen atom, cyclized efficiently at
room temperature in the presence of potassium tert-butox-
ide to give high yields of the corresponding lactams 3a
and 3c. On the other hand, compounds 5b and 5d, which
have a methoxy group attached to the nitrogen, required
refluxing of the reaction mixture for 72 hours to give good
yields of the final products (Scheme 4). These results
We had previously observed a similar behavior in the re-
action of α,β-unsaturated esters with N-sulfinyl amines
bearing a remote olefin moiety; that is, no tandem process
occurred, but the reaction stopped at the CM step. On the
Synthesis 2012, 44, 1863–1873
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Tandem Reaction for the Synthesis of α,α-Difluorinated Lactams
1865
show that the nucleophilicity of the potassium amides stereoselectivity at the newly created stereocenter (Table
from substrates 5a and 5c bearing a PMP group is higher 2, entries 3, 4). Unfortunately, it was not possible to sepa-
than that of their counterparts containing a methoxy group rate the resulting mixtures of diastereoisomers.
(5b and 5d).
Table 2 Asymmetric Tandem CM–IMAMR with SAMP-Derived
Amides 1e and 1f
R1
F
F
O
NH
O
F
( )n
O
F
( )n
*
O
t-BuOK
F
OEt
R2
O
( )n
N
R1
THF
O
OEt
F
N
O
F
SAMP
Ru-I (5 mol%)
O
SAMP
+
5a (n = 1, R1 = PMP)
5b (n = 1, R1 = OMe)
5c (n = 2, R1 = PMP)
5d (n = 2, R1 = OMe)
3a (4 h, r.t., 97%)
3b (72 h, reflux, 80%)
3c (6 h, r.t., 79%)
N
Ti(Oi-Pr)4 (10 mol%)
3
F
H
+
R2
( )n
CH2Cl2, heat
3d (72 h, reflux, 60%)
SAMP
NH
2a (R2 = OEt)
2b (R2 = Me)
O
1e (n = 1)
1f (n = 2)
Scheme 4 IMAMR of fluorinated unsaturated amides 5a–d
O
F
R2
( )n
F
Next, we examined the asymmetric synthesis of fluorinat-
ed lactams. In our first approach, our strategy involved the
use of a chiral auxiliary attached to the amide nitrogen.
Enders’ hydrazones were the auxiliaries of choice, be-
cause they had previously been employed, with satisfacto-
ry results, in Michael-type additions,16 despite the fact that
they are rarely used as chiral sources of nucleophilic nitro-
gen. Furthermore, the presence of a second nitrogen atom
should enhance the nucleophilicity of the amide nitrogen
in the cyclization step.
5
drc
Entry Reactants
Time Product 3
(h)
Product 5
[yielda,b (%)] [yielda (%)]
1
2
3
4
1e
1f
1e
1f
2a
2a
2b
2b
3
4
8
8
–
5e (75)
–
–
–
5f (64)
3k (58)
3l (62)
–
–
51:49
59:41
The starting amides 1e and 1f, with the (2S)-2-(methoxy-
methyl)pyrrolidine-1-amino (SAMP) moiety as a chiral
auxiliary, were prepared by following an analogous pro-
cedure to that used to prepare the non-chiral compounds
(Scheme 5).
a Isolated yields after flash column chromatography.
b Combined yields of two diastereoisomers.
c Determined by GC/MS.
Because compounds 5e and 5f did not cyclize under acidic
conditions, we decided to activate the amide deproton-
ation with a base. The results are summarized in Table 3.
OMe
O
F
F
1. (COCl)2, CH2Cl2
DMF (cat.)
Initially, we treated 5e (n = 1) with either potassium tert-
butoxide or lithium hexamethyldisilazide (LiHMDS) at 0
°C, but we found it to be totally inert under these condi-
tions (Table 3, entries 1 and 2). At room temperature, the
cyclized product 3i was obtained in 18% yield as a 59:41
mixture of diastereoisomers (entry 3). It was necessary to
heat the reaction mixture at 70 °C to obtain 3i in good
yield and with a slightly improved selectivity (entry 4).
When tetrabutylammonium fluoride (TBAF) was used as
a base, the reactivity of 5e changed markedly.17 Even at
–78 °C, cyclization occurred in 64% yield to give a nearly
1:1 mixture of diastereoisomers (entry 5). The same
IMAMR at room temperature gave a 71:29 mixture of the
diastereoisomeric pyrrolidinones 3i (entry 6), and the best
result in terms of selectivity (dr = 75:25) was achieved at
70 °C (entry 7). When these conditions were applied to the
formation of fluorinated piperidinones 3j (entries 8–10),
the best result was obtained at 70 °C, when 3j was isolated
in 77% yield as a 80:20 mixture of diastereoisomers (entry
10).
F
N
OH
( )n
N
F
H
( )n
2. Et3N, SAMP-NH2
DMAP (cat.)
O
4a,b
1e (n = 1, 35%)
1f (n = 2, 45%)
MeO
N
SAMP-NH2
H2N
Scheme 5 Preparation of (2S)-2-(methoxymethyl)pyrrolidine-1-
amine (SAMP)-derived starting amides 1e and 1f
Substrates 1e and 1f were subjected to tandem reaction
with the appropriate α,β-unsaturated derivative 2 in the
presence of catalyst Ru-I and titanium(IV) tetraisopro-
poxide as a co-catalyst in refluxing dichloromethane. As
in the case of the racemic substrates, when ethyl acrylate
(2a) was used to generate the Michael acceptor, the CM
products 5e and 5f were obtained in good yields (Table 2,
entries 1, 2). Again, the use of methyl vinyl ketone (2b) as
the conjugated partner allowed us to perform a tandem
CM–IMAMR process to give the corresponding nitrogen
heterocycles 3k and 3l in moderate yields but with poor
These results suggest that cyclization through the
IMAMR is reversible, and at higher temperatures the for-
mation of the thermodynamic product is favored (longer
reaction times led to decomposition products). Unfortu-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1863–1873

1866
S. Fustero et al.
SPECIAL TOPIC
catalyst. As expected, because the Michael acceptors were
α,β-unsaturated esters, the IMAMR did not occur sponta-
neously, and the CM products 5g–j were formed in mod-
erate-to-good yields after refluxing for five hours in
dichloromethane (Scheme 6).
Table 3 Base-Promoted Cyclization of Substrates 5e and 5f
SAMP
NH
F
( )n
O
F
O
F
F
O
OEt
base (1.2 equiv)
THF
*
O
N
( )n
OEt
SAMP
Table 4 Base-Promoted Cyclization of Substrates 5g–j
5e (n = 1)
5f (n = 2)
3i (n = 1)
3j (n = 2)
R1
F
O
F
O
F
F
NH
( )n
*
drb
Entry Substrate Base
Temp Time Product 3
O
base (2 equiv)
THF
[yielda (%)]
R*
(°C)
(h)
O
N
( )n
R*
R1
1
2
5e
5e
5e
5e
5e
5e
5e
5f
5f
5f
t-BuOK
LiHMDS
LiHMDS
LiHMDS
TBAF
0
0
4
6
5
4
8
5
1
8
4
1
–
–
3m–p
5g–j
R* = (1R,2S,5R)-(–)-8-phenylmenthyl
–
–
3
r.t.
70
–78
r.t.
70
0
3i (18)
3i (84)
3i (67)
3i (70)
3i (70)
3j (64)
3j (70)
3j (77)
59:41
62:38
52:48
71:29
75:25
70:30
76:24
80:20
drb
Entry Substrate Base
Temp Time Product
[yielda (%)]
4
(°C)
(h)
5
1
2
5g
5g
5g
5g
5g
5g
5h
5h
5h
5h
5h
5h
5i
t-BuOK
LiHMDS
TBAF
r.t.
r.t.
6
6
3m (51)
3m (70)
3m (87)
3m (65)
3m (23)
3m (85)
3n (46)
3n (30)
3n (85)
3n (34)
3n (14)
3n (64)
3o (67)
3p (69)
62:38
67:33
70:30
75:25
78:32
83:17
51:49
57:43
53:47
63:37
61:39
57:43
65:35
67:33
6
TBAF
7
TBAF
3
r.t.
12
6
8
TBAF
4
t-BuOK
LiHMDS
TBAF
–78
–78
–78
r.t.
9
TBAF
r.t.
70
5
10
24
10
10
10
24
24
48
48
48
10
TBAF
6
a Combined yields of two diastereoisomers.
b Determined by GC/MS.
7
t-BuOK
LiHMDS
TBAF
8
r.t.
nately, we were unable to separate the diastereoisomeric
mixtures of compounds 3i or 3j.
9
r.t.
10
11
12
13
14
t-BuOK
LiHMDS
TBAF
–78
–78
–78
0
In the next step of our study, we introduced a chiral auxil-
iary into the Michael acceptor. We decided to use 8-
phenylmenthyl acrylate as the conjugated partner, since 8-
phenylmenthol-derived crotonates have been efficiently
employed in other intermolecular aza-Michael addi-
tions.18 Thus, the starting fluorinated amides 1 were treat-
ed with the chiral acrylate 2c in the presence of ruthenium
catalyst Ru-I and titanium(IV) tetraisopropoxide as a co-
TBAF
5j
TBAF
0
a Combined yields of two diastereoisomers.
b Determined by 19F NMR integration.
R1
O
Ru-I (5 mol%)
Ti(Oi-Pr)4 (10 mol%)
O
F
F
R1
O
NH
N
O
+
H
F
R*
( )n
CH2Cl2, reflux, 5 h
( )n
R*
F
2c
1a (n = 1, R1 = PMP)
1c (n = 2, R1 = PMP)
1b (n = 1, R1 = OMe)
1d (n = 2, R1 = OMe)
5g (87%)
5h (89%)
5i (46%)
5j (38%)
R* = (–)-8-phenylmenthyl
O
Ph
Scheme 6 Preparation of 8-phenylmenthol-derived unsaturated amides 5g–j
Synthesis 2012, 44, 1863–1873
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Tandem Reaction for the Synthesis of α,α-Difluorinated Lactams
1867
aqueous ceric ammonium molybdate solution or KMnO4 stain.
Flash column chromatography was performed with the indicated
solvents on silica gel 60 (particle size 0.040–0.063 mm). 1H, 13C and
19F NMR spectra were recorded on Bruker AC-300 MHz and AC-
500 MHz spectrometers. Chemical shifts are given in ppm (δ) with
reference to the residual proton resonances of the solvents. Cou-
pling constants (J) are given in hertz (Hz). High-resolution mass
spectra were recorded on an ABSciex TRIPLETOF-5600 spectro-
meter in the ESI or EI mode.
Next, we completed the base-mediated cyclization of
compounds 5g–j; the results are summarized in Table 4.
Initially, we attempted to cyclize amide 5g (n = 1;
R1 = PMP) with various bases at room temperature (Table
4, entries 1–3). TBAF was found to be the best of these
bases, giving pyrrolidinone 3m in 87% yield as a 70:30
mixture of inseparable diastereoisomers (entry 3). The
same reactions were then carried out at –78 °C with simi-
lar results (entries 4–6); again the best yield and diastereo-
selectivity were achieved with TBAF (Table 4, entry 6).
Compound 5h (n = 2; R1 = PMP) also gave inseparable
mixtures of diastereoisomeric piperidinones 3n with low
selectivities, regardless of the temperature or the base em-
ployed (entries 7–12). With substrate 5i (n = 1;
R1 = OMe) or 5j (n = 2; R1 = OMe), the IMAMR did not
take place at –78 °C, highlighting the lower reactivity of
these fluorinated amides compared with 5g and 5h, which
contain a PMP protecting group. For compound 5i and 5j,
cyclization occurred at 0 °C to give the corresponding N-
heterocycles 3o and 3p in good yields but low diastereose-
lectivities (entries 13 and 14).
Fluorinated Amides 1; General Procedure
A catalytic amount of DMF and a 2.0 M soln of oxalyl chloride in
CH2Cl2 (0.74 mL, 1.47 mmol) were added dropwise to a soln of car-
boxylic acid 4a or 4b (1.47 mmol) in CH2Cl2 (8 mL) at 0 °C. The
mixture was then stirred at r.t. for 1 h then cooled to 0 °C. A soln of
Et3N (1.62 mmol), the appropriate amine (1.62 mmol), and a
catalylic amount of DMAP in CH2Cl2 (3 mL) was added. The result-
ing mixture was stirred at r.t. for 5 h before the reaction was
quenched with 3 M aq HCl (10 mL). The mixture was extracted
with CH2Cl2 (3 × 10 mL) and the extracts were washed with brine
(10 mL), dried (Na2SO4), and concentrated under reduced pressure
to give a crude product that was purified by flash column chroma-
tography.
2,2-Difluoro-N-(4-methoxyphenyl)pent-4-enamide (1a)
White solid; yield: 142 mg (40%); mp 76–78 °C.
3
1H NMR (300 MHz, CDCl3): δ = 2.95 (tdt, JHF = 31.5 Hz,
Finally, we removed the nitrogen-protecting group from
compound 3m by treating the mixture of diastereoisomer-
ic pyrrolidinones with an excess of cerium(IV) ammoni-
um nitrate for five days in order to produce total
conversion. After the reaction had been quenched with
hydrochloric acid, the difluorinated pyrrolidinones 6 were
obtained in moderate yield, again as an inseparable mix-
ture of diastereoisomers (Scheme 7).
3JHF = 16.9 Hz, 4JHF = 2.4 Hz, 2 H), 3.01 (s, 3 H), 5.26–5.34 (m, 2
H), 5.78 (tdd, J = 31.5 Hz, 3J = 17.3 Hz, J = 10.2 Hz, 1 H), 6.89
(td, 2J = 15.9 Hz, 3J = 9.0 Hz, 3J = 4.5 Hz, 2 H), 7.46 (td, 2J = 15.9
Hz, 3J = 9.0 Hz, 3J = 4.5 Hz, 2 H), 7.87 (br s, 1 H).
3
3
13C NMR (75.5 MHz, CDCl3): δ = 38.9 (t, JCF = 23.0 Hz), 55.9,
114.7, 117.6 (t, JCF = 254.5 Hz), 122.4, 127.5 (t, JCF = 5.6 Hz),
2
1
3
129.3, 157.7, 161.5 (t, 2JCF = 28.3 Hz).
3
19F NMR (282.4 MHz, CDCl3): δ = –105.9 (td, JHF = 34.7 Hz,
3JHF = 16.9 Hz, 4JHF = 2.9 Hz 2 F).
F
HRMS (ESI): m/z [M + H+] calcd for C12H14F2NO2: 242.0993;
F
O
F
1. Ce(NH4)2(NO3)6
MeCN–H2O, 0 °C to r.t.
O
F
found: 242.0998.
R*
*
O
R*
*
N
2. 3 M HCl
O
N
2,2-Difluoro-N-methoxypent-4-enamide (1b)
Brown oil; yield: 107 mg (44%).
PMP
3m
H
6 (54%)
1H NMR (300 MHz, CDCl3): δ = 2.86 (tdt, 3J = 33.6 Hz, 3JHF = 16.8
Hz, 3J = 2.4 Hz, 2 H), 3.81 (s, 3 H), 5.25–5.31 (m, 2 H), 5.72 (m, 1
R* = (1R,2S,5R)-(–)-8-phenylmenthyl
H).
Scheme 7 N-Deprotection of pyrrolidinone 3m
2
13C NMR (75.5 MHz, CDCl3): δ = 38.9 (t, JCF = 23.5 Hz), 65.0,
117.4 (t, 1JCF = 253.7 Hz), 122.7, 127.0 (t, 3JCF = 5.5 Hz), 161.4 (t,
2JCF = 28.6 Hz).
In summary, we synthesized a new family of fluorinated
γ- and δ-lactams by means of a CM–IMAMR sequence.
With conjugated ketones as the Michael acceptors, the
process can be performed in a tandem fashion, showing
that weak nucleophiles such as amides can participate in
such processes in the presence of a Lewis acid. When es-
ters were used as the conjugated partners, a step-by-step
protocol with a base-promoted IMAMR was necessary.
The asymmetric version of this sequence was also per-
formed by introducing a chiral auxiliary on either at the
nitrogen nucleophile or the Michael acceptor. The asym-
metric reaction generally provided good yields and, in the
best cases, moderate diastereoselectivities.
2
19F NMR (282.4 MHz, CDCl3): δ = –106.8 (dt, JFF = 242.9 Hz,
3JHF = 16.8 Hz, 2 F).
HRMS (ESI): m/z [M + Na]+ calcd for C6H9F2NNaO2: 188.0499;
found: 188.0500.
2,2-Difluoro-N-(4-methoxyphenyl)hex-5-enamide (1c)
Brown solid; yield: 143 mg (38%); mp 70–74 °C.
1H NMR (300 MHz, CDCl3): δ = 2.29 (m, 4 H), 3.80 (s, 3 H), 5.50
(m, 2 H), 5.81 (m, 1 H), 6.89 (td, 2J = 15.9 Hz, 3J = 9.3 Hz, 3J = 4.5
Hz, 2 H), 7.47 (td, 2J = 15.9 Hz, 3J = 9.0 Hz, 3J = 4.5 Hz, 2 H), 7.89
(br s, 1 H).
3
13C NMR (75.5 MHz, CDCl3): δ = 26.3 (t, JCF = 4.7 Hz), 33.5 (t,
1
2JCF = 23.3 Hz), 55.9, 114.7, 118.5 (t, JCF = 253.4 Hz), 116.2,
122.3, 129.3, 136.3, 157.6, 161.9 (t, 2JCF = 28.6 Hz).
3
19F NMR (282.4 MHz, CDCl3): δ = –106.0 (td, JHF = 32.0 Hz,
Reactions were carried out under argon unless otherwise indicated.
The solvents were purified before use: THF was distilled from
Na/benzophenone; CH2Cl2 and MeCN were distilled from CaH2.
The reactions were monitored by TLC on 0.25-mm precoated silica
gel plates. Visualization was carried out with UV radiation and
3JHF = 15.5 Hz, 4JHF = 2.9 Hz, 2 F).
HRMS (EI): m/z [M+] calcd for C13H15F2NO2: 255.1071; found:
255.1060.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1863–1873

1868
S. Fustero et al.
SPECIAL TOPIC
2,2-Difluoro-N-methoxyhex-5-enamide (1d)
Ethyl [4,4-Difluoro-1-(4-methoxyphenyl)-5-oxopyrrolidin-2-
yl]acetate (3a)
Brown oil; yield: 158 mg (brown oil).
Yellow solid: yield: 30 mg (97%); mp 70–85 °C.
1H NMR (300 MHz, CDCl3): δ = 2.21 (m, 5 H), 3.83 (s, 3 H), 5.05
(m, 2 H), 5.78 (m, 1 H).
1H NMR (300 MHz, CDCl3): δ = 1.19 (t, 3J = 7.1 Hz, 3 H), 2.35–
2.50 (m, 2 H), 2.70 (dd, 2J = 18.0 Hz, 3J = 3.0 Hz, 1 H), 2.88 (dtd,
J = 31.0, J = 22.3 Hz, J = 10.5 Hz, 1 H), 3.81 (s, 3 H), 4.05 (d,
3
13C NMR (75.5 MHz, CDCl3): δ = 25.9 (t, JCF = 4.8 Hz), 33.6 (t,
2JCF = 22.9 Hz), 65.0, 118.1 (t, 1JCF = 252.4 Hz), 116.1, 136.1, 161.7
1
3J = 7.1 Hz, 2 H), 4.47–4.57 (m, 1 H), 6.94 (ddd, J = 15.9 Hz,
(t, 2JCF = 28.9 Hz).
2J = 9.0 Hz, 3J = 4.5 Hz, 2 H), 7.29 (ddd, 1J = 15.9 Hz, 2J = 9.0 Hz,
19F NMR (282.4 MHz, CDCl3): δ = –107.2 (t, J = 14.9 Hz, 2 F).
3J = 4.5 Hz, 2 H).
HRMS (ESI): m/z [M+] calcd for C7H11F2NO2: 179.0758; found:
179.0773.
2
13C NMR (75.5 MHz, CDCl3): δ = 14.4, 36.9 (t, JCF = 22.4 Hz),
3
38.5, 51.9 (q, JCF = 5.2 Hz), 55.9, 61.5, 115.1, 117.7 (t,
2
1JCF = 249.6 Hz), 126.1, 128.1, 159.2, 162.9 (t, JCF = 30.9 Hz),
2,2-Difluoro-N-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]pent-4-
enamide (1e)
170.0.
2
19F NMR (282.4 MHz, CDCl3): δ = –100.8 (dtd, JFF = 271.8 Hz,
Brown oil: yield: 128 mg (35%); [α]D25 –14.3 (c 1.0, CHCl3).
4
2
3JHF = 32.6 Hz, JHF = 4.5 Hz, 1 F), –105.80 (dq, JFF = 271.6 Hz,
1H NMR (300 MHz, CDCl3): δ = 1.38–1.50 (m, 1 H), 1.60–1.70 (m,
2 H), 1.75–1.87 (m, 1 H), 2.59–2.73 (m, 3 H), 2.92–3.09 (m, 2 H),
3.13 (s, 3 H), 3.20–3.27 (m, 2 H), 5.04–5.10 (m, 2 H), 5.48–5.62 (m,
1 H), 7.80 (br s, 1 H).
3JHF = 16.5 Hz, 4JHF = 10.4 Hz, 1 F).
HRMS (ESI): m/z [M + Na]+ calcd for C15H17F2NNaO4: 336.1023;
found: 336.1023.
2
13C NMR (75.5 MHz, CDCl3): δ = 21.1, 26.1, 38.5 (t, JCF = 24.1
Ethyl (4,4-Difluoro-1-methoxy-5-oxopyrrolidin-2-yl)acetate
Hz), 54.9, 58.9, 63.8, 74.8, 117.0 (t, 1JCF = 253.7 Hz), 121.5, 127.2
(t, 3JCF = 5.5 Hz), 162.2 (t, 2JCF = 27.3 Hz).
(3b)
Brown oil: yield: 19 mg (80%).
1
19F NMR (282.4 MHz, CDCl3): δ = –106.5 (dt, JFF = 252.7 Hz,
1H NMR (300 MHz, CDCl3): δ = 1.2 (t, 3J = 7.2 Hz, 3 H), 2.18–2.35
(m, 1 H), 2.45 (dd, 3JHF = 16.2 Hz, 3J = 8.1 Hz, 1 H), 2.66–2.88 (m,
2 H), 63.80 (s, 3 H), 4.08–4.17 (m, 2 H), 4.21–4.31 (m, 1 H).
3JHF = 15.5 Hz, 1 F), –107.4 (dt, 1JFF = 253.7 Hz, 3JHF = 17.8 Hz, 1
F).
HRMS (ESI): m/z [M + H]+ calcd for C11H19F2N2O2: 249.1415;
found: 249.1412.
2
13C NMR (75.5 MHz, CDCl3): δ = 14.5, 35.3 (t, JCF = 23.5 Hz),
37.6 (t, 4JCF = 1.6 Hz), 48.1, 49.9 (t, 3JCF = 2.7 Hz), 61.8, 63.4, 115.8
(t, 1JCF = 253.0 Hz), 169.9.
2,2-Difluoro-N-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]hex-5-
enamide (1f)
19F NMR (282.4 MHz, CDCl3): δ = –102.1 (dddd, 2JFF = 270.6 Hz,
4
2
3JHF = 16.6 Hz, JHF = 4.2 Hz, 1 F), –104.8 (ddd, JFF = 270.6 Hz,
Brown oil: yield: 174 mg (45%); [α]D25 –20.6 (c 1.0, CHCl3).
3JHF = 14.9 Hz, 3JHF = 12.9 Hz, 1 F).
1H NMR (500 MHz, CDCl3): δ = 1.62 (ddd, J = 21.6 Hz, J = 12.0
Hz, J = 3.3 Hz, 1 H), 1.86 (ddd, J = 17.7 Hz, J = 9.6 Hz, J = 4.8 Hz,
HRMS (ESI): m/z [M + H]+ calcd for C9H14F2NO4: 238.0885;
3
found: 238.0882.
2 H), 1.96–2.03 (m, 1 H), 2.13–2.28 (m, 4 H), 2.88 (dd, J = 10.2
Hz, 3J = 5.1 Hz, 1 H), 3.13–3.46 (m, 4 H), 3.31 (s, 3 H), 5.02 (quint,
Ethyl [5,5-Difluoro-1-(4-methoxyphenyl)-6-oxopiperidin-2-
yl]acetate (3c)
Brown solid: yield: 26 mg (79%); mp 105–108 °C.
1H NMR (300 MHz, CDCl3): δ = 1.19 (t, 3J = 7.2 Hz, 3 H), 1.99–
2.12 (m, 1 H), 2.28–2.61 (m, 5 H), 3.81 (s, 3 H), 4.02 (ddd,
3JHF = 14.2 Hz, J = 7.2 Hz, J = 1 Hz, 2 H), 4.24–4.32 (m, 1 H),
6.90–6.96 (m, 2 H), 7.09–7.14 (m, 2 H).
2 H), 5.74–5.84 (m, 1 H).
3
13C NMR (125.7 MHz, CDCl3): δ = 21.4, 25.9 (t, JCF = 4.7 Hz),
2
26.2, 33.4 (t, JCF = 23.1), 55.3, 59.3, 64.0, 74.8, 115.7, 118.6 (t,
1JCF = 252.9 Hz), 136.2, 162.7 (t, 2JCF = 27.6 Hz).
19F NMR (282.4 MHz, CDCl3): δ = –100.54 (J = 16.6 Hz), –106.9
to –107.1 (m, 2 F).
HRMS (ESI): m/z [M + H]+ calcd for C12H21F2N2O2: 263.1566;
found: 263.1558.
13C NMR (75.5 MHz, CDCl3): δ = 14.4, 24.1 (t, 3JCF = 5.2 Hz), 29.3
(t, 2JCF = 23.2 Hz), 38.3, 55.8, 57.2, 61.4, 112.6 (t, 1JCF = 244.5 Hz),
115.2, 129.0, 131.5, 159.5, 162.2 (t, 2JCF = 30.0 Hz), 170.3.
Difluoropyrrolidones 3 and Difluoro Amides 5 (Tandem Proto-
col); General Procedure
2
19F NMR (282.4 MHz, CDCl3): δ = –100.7 (dt, JFF = 282.4 Hz,
3JHF = 14.1 Hz, 1 F), –101.8 (dt, 2JFF = 280.1 Hz, 3JHF = 11.3 Hz, 1
Ti(Oi-Pr)4 (0.38 mmol) or BF3·OEt2 (0.38 mmol) was added to a
soln of amide 1 (0.38 mmol) in CH2Cl2 (3.8 mL) in a sealed tube and
the mixture was stirred for 5 min at r.t. The α,β-unsaturated com-
pound 2 (3 equiv) and Hoveyda–Grubbs second-generation rutheni-
um catalyst Ru-I (0.038 mmol, 10 mol%) were added and the
mixture was heated at 60 °C until all the starting material was con-
sumed (TLC; 5–10 h). The crude mixture was cooled to r.t., concen-
trated, and purified by flash column chromatography.
F).
HRMS (ESI): m/z [M+] calcd for C16H19F2NO4: 327.1282; found:
327.1295.
Ethyl (5,5-Difluoro-1-methoxy-6-oxopiperidin-2-yl)acetate (3d)
Brown oil: yield: 15 mg (60%).
1H NMR (300 MHz, CDCl3): δ = 1.28 (t, 3J = 7.2 Hz, 3 H), 1.88–
2.02 (m, 1 H), 2.15–2.36 (m, 3 H), 2.49 (dd, 2J = 15.9 Hz, 3J = 7.5
Base-Promoted Cyclization of Difluoro Amides 5; General Pro-
cedure
2
3
Hz, 1 H), 2.92 (dd, J = 15.9 Hz, J = 5.4 Hz, 1 H), 3.78 (s, 3 H),
4.78 (ddd, J = 21.3 Hz, J = 7.2 Hz, J = 1.8 Hz, 2 H), 4.26–4.35 (m,
1 H).
The appropriate base (1.2–3.0 equiv) was added to a soln of amide
5 (0.1 mmol) in THF (2 mL) and the mixture was stirred at the ap-
propriate temperature until the starting material was consumed. The
reaction was quenched with sat. aq NH4Cl (5 mL) and the mixture
was extracted with CH2Cl2 (3 × 5 mL). The extracts were concen-
trated and the resulting crude mixture was purified by flash column
chromatography.
13C NMR (75.5 MHz, CDCl3): δ = 14.5, 23.7 (t, 3JCF = 4.8 Hz), 26.9
(t, 2JCF = 23.1 Hz), 37.7, 56.5, 61.6, 62.4, 113.3 (t, 1JCF = 252.9 Hz),
155.2 (2JCF = 31.3 Hz), 170.6.
19F NMR (282.4 MHz, CDCl3): δ = –101.7 (t, J = 26.8 Hz, 2 F).
HRMS (EI): m/z [M + H]+ calcd for C10H16F2NO4: 252.1042; found:
252.1043.
Synthesis 2012, 44, 1863–1873
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Tandem Reaction for the Synthesis of α,α-Difluorinated Lactams
1869
3,3-Difluoro-1-(4-methoxyphenyl)-5-(2-oxopropyl)pyrrolidin-
2-one (3e)
3J = 32.5 Hz, 3JHF = 16.5 Hz, 4J = 8.1 Hz, 1 H), 2.59–2.78 (m, 1 H),
2.89 (dd,2J = 15.9 Hz, 3J = 5.1 Hz, 1 H), 3.15–3.33 (m, 6 H), 5.53
(dd, 2J = 16.5 Hz, 3J = 8.1 Hz, 1 H), 3.90 (dq, 2J = 16.8 Hz, 3J = 4.2
Hz, 1 H), 4.02–4.18 (m, 3 H).
Brown oil; yield: 66 mg (61%).
1H NMR (300 MHz, CDCl3): δ = 2.09 (s, 3 H), 2.19–2.34 (m, 1 H),
2.52–2.61 (m, 1 H), 2.81–2.99 (m, 1 H), 2.94 (dd, J = 16.6 Hz, J =
7.5 Hz, 1 H), 3.81 (s, 3 H), 4.52–4.62 (m, 1 H), 6.92 (ddd, 3J = 15.9
Hz, 4J = 9.0 Hz, 5J = 4.5 Hz, 2 H), 7.26 (ddd, 3J = 15.9 Hz, 4J = 9.0
Hz, 5J = 4.5 Hz, 2 H).
13C NMR (75.5 MHz, CDCl3): δ = 14.4, 14.5, 22.5, 22.5, 26.8, 26.9,
35.6 (t, 2JCF = 22.6 Hz), 35.8 (t, 2JCF = 21.8 Hz), 38.2 (d, 2JCF = 1.1
Hz), 38.6 (d, 2JCF = 1.5 Hz), 51.6 (t, 3JCF = 2.5 Hz), 51.7, 53.1, 53.6
(t, 3JCF = 2.6 Hz), 58.7, 58.9, 59.0, 59.7, 61.1, 61.2, 75.4, 75.8, 116.4
(t, 1JCF = 252.8 Hz), 116.6 (t, 1JCF = 250.5 Hz), 161.7 (t, 2JCF = 30.7
Hz), 161.9 (t, 2JCF = 30.2 Hz), 170.6, 170.9.
2
13C NMR (75.5 MHz, CDCl3): δ = 30.8, 35.9 (t, JCF = 22.3 Hz),
47.0, 51.1 (d, 3JCF = 2.8 Hz), 55.9, 115.2, 117.8 (t, 1JCF = 248.0 Hz),
125.8, 128.8, 128.0, 159.1, 162.4 (t, 2JCF = 28.5 Hz), 205.5.
19F NMR (282.4 MHz, CDCl3): δ (major) = –103.1 (dddd,
3
4
2JFF = 268.2 Hz, JHF = 28.2 Hz, JHF = 4.2 Hz, 1 F), –106.9 (dt,
19F NMR (282.4 MHz, CDCl3): δ = –100.34 (dtd, 2JFF = 271.6 Hz,
3
2JFF = 268.9 Hz, JHF = 16.9 Hz, 1 F); δ (minor) = –104.0 (dddd,
4
2
3JHF = 38.7 Hz, JHF = 4.2 Hz, 1 F), –106.38 (dq, JHF = 269.2 Hz,
3
4
2JFF = 265.6 Hz, JHF = 25.4 Hz, JHF = 3.7 Hz, 1 F), –106.3 (ddd,
3JHF = 16.3 Hz, 4JHF = 9.6 Hz, 1 F).
2JFF = 268.6 Hz, 3JHF = 17.8 Hz, 4JHF = 14.7 Hz, 1 F).
HRMS (ESI): m/z [M + H]+ calcd for C14H16F2NO3: 284.1093;
found: 284.1085.
HRMS (ESI): m/z [M]+ calcd for C14H22F2N2O4: 320.1548; found:
320.1561.
3,3-Difluoro-1-methoxy-5-(2-oxopropyl)pyrrolidin-2-one (3f)
Ethyl {5,5-Difluoro-1-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]-
6-oxopiperidin-2-yl}acetate (3j)
Brown oil; yield: 46 mg (58%).
1H NMR (300 MHz, CDCl3): δ = 2.12–2.18 (m, 1 H), 2.22 (s, 3 H),
(s, 3 H), 2.58 (dd, 3JHF = 18.0 Hz, 4JHF = 8.1 Hz, 1 H), 2.73–2.73 (m,
1 H), 3.12 (dd,2J = 17.8 Hz, 3J = 4.8 Hz, 1 H), 3.82 (s, 3 H), 4.34–
4.43 (m, 1 H).
Brown oil; yield: 26 mg (77%; 80:20 mixture of diastereoisomers).
1H NMR (300 MHz, CDCl3): δ = 1.22–1.44 (m, 1 H), 1.29 (t, 3J =
7.2 Hz, 3 H), 1.58–2.34 (m, 5 H), 2.43 (dd, J = 15.6 Hz, J = 7.5 Hz,
1 H), 2.96 (dd, J = 15.6 Hz, J = 5.5 Hz, 1 H), 3.06–3.43 (m, 4 H),
3.31 (s, 3 H), 3.51 (q, J = 7.7 Hz, 1 H), 3.85–3.94 (m, 1 H), 4.12–
4.27 (m, 2 H), 4.16 (q, J = 7.2 Hz, 2 H).
13C NMR (75.5 MHz, CDCl3): δ = 14.6, 23.1, 24.1, 27.5, 29.4 (t,
2JCF = 22.9 Hz), 39.1, 53.1, 59.1, 59.5, 59.8, 61.2, 75.9, 113.2 (t,
1JCF = 248.6 Hz), 161.1 (t, 2JCF = 29.6 Hz), 171.4.
2
13C NMR (75.5 MHz, CDCl3): δ = 30.8, 35.5 (t, JCF = 23.3 Hz),
46.3, 46.3, 48.9 (t, 3JCF = 2.9 Hz), 63.0, 115.5 (t, 1JCF = 252.4 Hz),
205.1.
19F NMR (282.4 MHz, CDCl3): δ = –100.34 (dtd, 2JFF = 271.6 Hz,
4
2
3JHF = 34.4 Hz, JHF = 4.2 Hz, 1 F), –106.36 (dq, JFF = 271.5 Hz,
3JHF = 18.9 Hz, 4JHF = 9.6 Hz, 1 F).
3
19F NMR (282.4 MHz, CDCl3): δ = –101.8 (dd, JHF = 29.1 Hz,
HRMS (ESI): m/z [M + Na]+ calcd for C8H11F2NNaO3: 230.0605;
found: 230.0607.
4JHF = 13.6 Hz, 2 F).
HRMS (EI): m/z [M + H]+ calcd for C15H25F2N2O4: 335.1777;
found: 335.1785.
3,3-Difluoro-1-(4-methoxyphenyl)-6-(2-oxopropyl)piperidin-2-
one (3g)
(2′S)-3,3-Difluoro-2′-(methoxymethyl)-5-(2-oxopropyl)-1,1′-bi-
pyrrolidin-2-one (3k)
Brown oil; yield: 64 mg (58%; 51:49 mixture of diastereoisomers).
1H NMR (300 MHz, CDCl3): δ = 1.37–1.44 (m, 1 H), 1.51–1.59 (m,
1 H), 1.67–1.77 (m, 2 H), 1.84–1.91 (m, 1 H), 1.92–1.98 (m, 1 H),
Brown oil; yield: 58 mg (51%) .
1H NMR (300 MHz, CDCl3): δ = 1.91–2.00 (m, 4 H), 2.29–2.46 (m,
3 H), 2.55–2.71 (m, 2 H), 3.81 (s, 3 H), 4.32–4.40 (m, 1 H), 6.92
3
4
(ddd, J = 15.3 Hz, J = 9.0 Hz, 5J = 4.5 Hz, 2 H), 7.09 (ddd,
3J = 15.3 Hz, 4J = 9.0 Hz, 5J = 4.5 Hz, 2 H).
2
1.99–2.12 (m, 4 H), 2.18 (d, J = 4.0 Hz, 6 H), 2.49 (td, J = 37.5
3
13C NMR (75.5 MHz, CDCl3): δ = 24.4 (t, JCF = 5.2 Hz), 29.5 (t,
2
Hz,3 J = 8.5 Hz, 2 H), 2.67–2.78 (m, 2 H), 3.05 (td, J = 16.0 Hz,
1
2JCF = 23.1 Hz), 30.9, 46.7, 55.9, 56.3, 112.7 (t, JCF = 244.3 Hz),
3J = 3.5 Hz, 1 H), 3.13–3.18 (m, 3 H), 3.21–3.24 (m, 1 H), 3.28 (s,
115.2, 129.0, 131.6, 159.5, 162.4 (t, 2JCF = 29.9 Hz), 205.5.
19F NMR (282.4 MHz, CDCl3): δ = –101.1 (t, 3J = 14.7 Hz, 2 F).
2
4 H), 3.29–3.30 (m, 2 H), 3.32 (s, 4 H), 3.57 (dd, J = 16.5 Hz,
3J = 8.5 Hz, 1 H), 3.89 (ddd, J = 23.3 Hz, J = 7.75 Hz, J = 3.5 Hz, 1
H), 4.08–4.17 (m, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C15H18F2NO3: 298.1249;
found: 298.1253.
13C NMR (75.5 MHz, CDCl3): δ = 22.4, 22.7, 26.5, 26.7, 30.5, 30.5,
35.7 (t, 2JCF = 22.2 Hz), 35.9 (t, 2JCF = 21.6 Hz), 46.7 (d, 3JCF = 1.1
3
3
3,3-Difluoro-1-methoxy-6-(2-oxopropyl)piperidin-2-one (3h)
Brown oil; yield: 41 mg (49%).
Hz), 47.4 (d, JCF = 1.5 Hz), 50.9 (t, JCF = 2.6 Hz), 51.6, 52.9 (t,
3JCF = 2.5 Hz), 53.1, 58.8, 58.8, 58.9, 58.9, 74.8, 76.3, 116.5 (t,
1JCF = 250.4 Hz), 116.6 (t, JCF = 254.2 Hz), 161.6 (t, JCF = 30.5
1
2
1H NMR (300 MHz, CDCl3): δ = 1.79–1.90 (m, 1 H), 2.09–2.15 (m,
Hz), 161.8 (t, 2JCF = 29.6 Hz), 205.8, 205.8.
2
1 H), 2.17–2.22 (m, 4 H), 2.23–2.29 (m, 1 H), 2.52 (dd, J = 17.4
Hz, 3J = 6.9 Hz, 1 H), 3.06 (dd, 2J = 17.4 Hz, 3J = 5.4 Hz, 1 H), 3.71
19F NMR (282.4 MHz, CDCl3): δ (first isomer) = –102.6 (dtd,
2JFF = 268.3 Hz, JHF = 29.9 Hz, JHF = 4.5 Hz, 1 F), –106.6
3
4
(s, 3 H), 4.36–4.45 (m, 1 H).
(2JFF = 268.3 Hz, JHF = 31.1 Hz, JHF = 15.5, 2 F); δ (second iso-
mer) = –103.2 (dtd, 2JFF = 268.7 Hz, 3JHF = 27.4 Hz, 4JHF = 4.0 Hz,
1 F), –107.2 (2JFF = 268.7 Hz, 3JHF = 32.8 Hz, 4JHF = 16.7, 2 F).
3
4
3
13C NMR (75.5 MHz, CDCl3): δ = 23.7 (t, JCF = 5.0 Hz), 29.5 (t,
1
2JCF = 23.0 Hz), 30.7, 45.8, 55.2, 61.7, 113.3 (t, JCF = 246.5 Hz),
159.0 (t, 3JCF = 30.4 Hz), 205.3.
HRMS (ESI): m/z [M + H]+ calcd for C13H21F2N2O3: 291.1514;
found: 291.1512.
19F NMR (282.4 MHz, CDCl3): δ = –101.7 (t, J = 12.7 Hz, 2 F).
HRMS (ESI): m/z [M + H]+ calcd for C9H14F2NO3: 222.0936;
found: 222.0928.
3,3-Difluoro-1-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]-6-(2-
oxopropyl)piperidin-2-one (3l)
Ethyl [(2′S)-4,4-Difluoro-2′-(methoxymethyl)-5-oxo-1,1′-bipyr-
rolidin-2-yl]acetate (3i)
Brown oil: yield: 22 mg (70%; 75:25 mixture of diastereoisomers).
1H NMR (300 MHz, CDCl3): δ = 1.25 (t, 3J = 7.2 Hz, 3 H), 1.32–
1.53 (s, 1 H), 1.60–1.75 (m, 1 H), 1.81–2.27 (m, 3 H), 2.40 (td,
Brown oil; yield: 72 mg (62%; 59:41 mixture of diastereoisomers).
1H NMR (300 MHz, CDCl3): δ = 1.33–1.39 (m, 1 H), 1.45–1.53 (m,
1 H), 1.55–1.61 (m, 1 H), 1.64–1.74 (m, 2 H), 1.81–1.87 (m, 2 H),
1.94–2.05 (m, 4 H), 2.10–2.16 (m, 2 H), 2.18 (m, 5 H), 2.28 (dd,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1863–1873

1870
S. Fustero et al.
SPECIAL TOPIC
J = 10.4 Hz, J = 3.3 Hz, 1 H), 2.49 (dd, J = 10.2 Hz, J = 4.8 Hz, 1
H), 3.03 (td, J = 9.5 Hz, J = 4.5 Hz, 1 H), 3.16 (dd, J = 10.2 Hz,
J = 2.4 Hz, 1 H), 3.24–3.26 (m, 2 H), 3.28 (s, 3 H), 3.29–3.10 (m, 1
H), 3.32 (s, 2 H), 3.41–3.45 (m, 1 H), 3.50 (dd, J = 14.9 Hz, J = 4.8
Hz, 1, H), 3.82–3.87 (m, 1 H), 4.14–4.20 (m, 1 H), 4.22–4.28 (m, 1
H).
HRMS (ESI): m/z [M + H]+ calcd for C30H38F2NO4: 514.2691;
found: 514.2717.
(1R,2S,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)cyclohexyl
(4,4-Difluoro-1-methoxy-5-oxopyrrolidin-2-yl)acetate (3o)
Brown oil: yield: 28 mg (67%; 65:35 mixture of diastereoisomers).
1H NMR (300 MHz, CDCl3): δ = 0.89 (d, J = 6.6 Hz, 3 H), 0.94–
1.01 (m, 1 H), 1.12–1.26 (m, 4 H), 1.28 (s, 3 H), 1.41–1.55 (m, 1 H),
1.60–1.85 (m, 3 H), 1.88–2.29 (m, 4 H), 2.56–2.72 (m, 1 H), 3.78
(s, 1 H), 3.81 (s, 3 H), 3.83–3.90 ( m, 1 H), 4.78–4.88 (m, 1 H),
7.08–7.17 (m, 1 H), 7.25–7.31 (m, 4 H).
13C NMR (75.5 MHz, CDCl3): δ = 22.5, 22.9, 24.0 (t, 4JCF = 5.2 Hz),
25.1 (t, 4JCF = 4.1 Hz), 26.5, 27.3, 29.2 (t, 2JCF = 22.8 Hz), 30.3 (t,
2JCF = 22.9 Hz), 30.4, 30.6, 46.5, 47.2, 50.3, 53.1, 56.6, 56.6, 58.6
3
3
(d, JCF = 11.3 Hz), 58.9 (d, JCF = 9.4 Hz), 59.6, 59.6, 74.8, 76.7,
1
1
113.1 (t, JCF = 245.0 Hz), 113.2 (t, JCF = 245.5 Hz), 161.1 (t,
2JCF = 30.3 Hz), 161.8 (t, 2JCF = 29.8 Hz), 205.5, 206.0.
13C NMR (75.5 MHz, CDCl3): δ = 22.2, 22.4, 22.5, 22.9, 26.5, 26.5,
2
30.5, 30.6, 31.6, 31.7, 34.7, 34.8, 35.2 (t, JCF = 23.7 Hz), 35.3 (t,
19F NMR (282.4 MHz, CDCl3): δ (major) = –101.1 (dtd,
4
4
2JCF = 23.1 Hz), 37.6 (d, JCF = 1.5 Hz), 37.9 (d, JCF = 1.2 Hz),
39.6, 39.7, 41.9, 41.9, 49.5, (t, 3JCF = 2.8 Hz), 49.7 (t, 3JCF = 2.7 Hz),
50.2, 50.4, 63.2, 63.3, 75.4, 75.4, 115.3 (t, 1JCF = 249.2 Hz), 115.4
(t, 1JCF = 252.5 Hz), 125.4, 125.6, 125.6, 125.7, 128.3, 128.4, 152.5,
3
4
2JFF = 271.7 Hz, JHF = 33.3 Hz, JHF = 4.2 Hz, 1 F), –106.2
3
(2JFF = 271.7 Hz, JHF = 16.6 Hz, 4JHF = 10.7, 1 F); δ (minor) =
–101.4 (dtd, 2JFF = 271.5 Hz, 3JHF = 31.9 Hz, 4JHF = 4.2 Hz, 1 F),
–105.7 (2JFF = 271.7 Hz, 3JHF = 16.8 Hz, 4JHF = 11.6, 1 F).
2
2
152.6, 158.6 (t, JCF = 31.4 Hz), 158.7 (t, JCF = 31.4 Hz), 169.1,
HRMS (ESI): m/z [M + H]+ calcd for C14H23F2N2O3: 305.1671;
found: 305.1662.
169.3.
19F NMR (282.4 MHz, CDCl3): δ (major) = –102.4 (dddd,
3
4
2J = 270.2 Hz, JHF = 27.6 Hz, JHF = 10.4 Hz, 1 F), –105.0 (ddd,
2JFF = 270.2 Hz, 3JHF = 17.9 Hz, 4JHF = 13.8 Hz, 1 F); δ (minor) =
–102.1 (dddd, 2JFF = 270.1 Hz, 3JHF = 27.8 Hz, 4JHF = 4.2 Hz, 1 F),
–104.5 (ddd, 2JFF = 270.1 Hz, 3JHF = 17.7 Hz, 4JHF = 13.8 Hz, 1 F).
(1R,2S,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)cyclohexyl
[4,4-Difluoro-1-(4-methoxyphenyl)-5-oxopyrrolidin-2-yl]ace-
tate (3m)
Brown oil: yield: 43 mg (85%; 83:17 mixture of diastereoisomers).
1H NMR (300 MHz, CDCl3): δ = 0.80–0.97 (m, 7 H), 1.12 (s, 3 H),
1.15–1.18 (m, 1 H), 1.21 (s, 3 H), 1.25 (d, J = 3.3 Hz, 2 H), 1.62–
1.71 (m, 4 H), 1.81–1.91 (m, 2 H), 1.98–2.07 (m, 1 H), 2.11–2.28
(m, 1 H), 2.76 (ddd, J = 31.8 Hz, J = 15.3 Hz, J = 7.8 Hz, 1 H), 3.85
(s, 3 H), 4.13–4.23 (m, 1 H), 4.76 (td, J = 11.3 Hz, J = 4.5 Hz, 1 H),
6.79 (t, 3J = 7.2 Hz, 1 H), 6.92–7-05 (m, 4 H).
HRMS (ESI): m/z [M + Na]+ calcd for C23H31F2NNaO4: 446.2123;
found: 446.2104.
(1R,2S,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)cyclohexyl
(5,5-Difluoro-1-methoxy-6-oxopiperidin-2-yl)acetate (3p)
Brown oil: yield: 30 mg (69%; 67:33 mixture of diastereoisomers).
1H NMR (300 MHz, CDCl3): δ = 0.85 (d, J = 6.6 Hz, 3 H), 0.90–
0.98 (m, 1 H), 1.08–1.18 (m, 4 H), 1.25 (s, 3 H), 1.42–1.46 (m, 1 H),
1.59–1.73 (m, 4 H), 1.76–1.87 (m, 2 H), 1.92–2.24 (m, 5 H), 3.68
(s, 3 H), 3.75–3.82 (m, 1 H), 4.71–4.81 (m, 1 H), 7.05–7.12 (m, 1
H), 7.21–7.28 (m, 4 H).
13C NMR (75.5 MHz, CDCl3): δ = 22.1, 22.6, 23.1, 23.4, 26.5, 26.6,
2
30.1, 30.5, 31.6, 32.3, 34.8, 34.9, 35.6 (t, JCF = 22.3 Hz), 35.7 (t,
2JCF = 23.3 Hz), 38.2, 38.3, 39.6, 39.8, 41.9, 42.0, 50.2, 50.3, 55.9,
55.9, 75.2, 75.4, 115.1, 117.7 (t, 1JCF = 249.2 Hz), 115.2, 117.7 (t,
1JCF = 249.2 Hz), 125.3, 125.4, 125.5, 126.6, 126.5, 128.1, 128.3,
128.4, 128.8, 128.9, 132.4, 132.5, 152.2, 152.2, 159.3, 159.4, 162.9
(t, 2JCF = 33.4 Hz), 163.0 (t, 2JCF = 30.9 Hz), 169.2, 169.4.
13C NMR (75.5 MHz, CDCl3): δ = 22.1, 22.2, 22.8, 22.9, 23.5 (t,
3JCF = 5.7 Hz), 23.7 (t, 3JCF = 5.2 Hz), 26.6, 26.6, 29.6 (t, 2JCF = 23.1
Hz), 29.8 (t, 2JCF = 23.0 Hz), 30.3, 30.3, 31.4, 31.6, 34.8, 34.9, 37.3,
37.8, 39.7, 39.8, 41.8, 41.9, 50.2, 50.4, 56.1, 56.6, 62.2, 62.5, 75.2,
2
19F NMR (282.4 MHz: δ (major) = –100.1 (dtd, JFF = 271.4 Hz,
4
2
3JHF = 16.3 Hz, JHF = 3.4 Hz, 1 F), –105.9 (ddd, JFF = 271.4 Hz,
1
1
4
75.5, 113.1 (t, JCF = 246.8 Hz), 113.3 (t, JCF = 246.8 Hz), 125.4,
125.5, 125.7, 125.7, 128.3, 128.4, 152.3, 152.6, 159.6 (t, 2JCF = 29.8
Hz), 159.8 (t, 2JCF = 28.2 Hz), 169.6, 169.9.
3JHF = 16.6 Hz, JHF = 10.7 Hz, 1 F); δ (minor) = –101.4 (dtd,
2JFF = 271.4 Hz, JHF = 15.3 Hz, JHF = 3.9 Hz, 1 F), –105.2 (ddd,
3
4
2JFF = 271.2 Hz, 3JHF = 17.4 Hz, 4JHF = 12.7 Hz, 1 F).
19F NMR (282.4 MHz, CDCl3): δ (major) = –102.3 (ddd,
HRMS (ESI): m/z [M + H]+ calcd for C29H36F2NO4: 500.2612;
found: 500.2617.
3
4
2JFF = 281.1 Hz, JHF = 22.1 Hz, JHF = 11.9 Hz, 1 F), –107.4 (t,
3JHF = 16.1 Hz, 1 F); δ (minor) = –100.9 (ddd, JFF = 277.0 Hz,
2
3JHF = 18.2 Hz, 4JHF = 12.1 Hz, 1 F), –107.1 (t, 3JHF = 16.3 Hz, 1 F).
(1R,2S,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)cyclohexyl
[5,5-Difluoro-1-(4-methoxyphenyl)-6-oxopiperidin-2-yl]ace-
tate (3n)
HRMS (ESI): m/z [M + H]+ calcd for C24H34F2NO4: 438.2450;
found: 438.2446.
Brown oil: yield: 33 mg (64%; 57:43 mixture of diastereoisomers).
1H NMR (CDCl3, 300 MHz, CDCl3): δ = 0.85–0.99 (m, 10 H),
1.17–1.34 (m, 15 H), 1.41–1.56 (m, 3 H), 1.61–1.80 (m, 7 H), 1.83–
1.97 (m, 5 H), 2.01–2.11 (m, 2 H), 2.24–2.41 (m, 7 H), 3.86 (s, 2 H),
3.90 (s, 3 H), 4.00–4.14 (m, 2 H), 4.71–4.82 (m, 2 H), 6.96–7.15 (m,
10 H), 7.20–7.28 (m, 6 H).
Ethyl (2E)-5,5-Difluoro-6-[(4-methoxyphenyl)amino]-6-oxo-
hex-2-enoate (5a)
Brown solid; yield: 107 mg (90%); mp 94–97 °C.
1H NMR (300 MHz, CDCl3): δ = 1.28 (t, 3J = 7.2 Hz, 3 H), 3.10 (tdd,
3JHF = 16.8 Hz, 3J = 7.5 Hz, 4J = 1.5 Hz, 2 H), 3.80 (s, 3 H), 4.19 (q,
J= 7.2 Hz, 2 H), 6.04 (dt, 3J = 15.7 Hz, 4J = 1.3 Hz, 1 H), 6.83–6.93
(m, 3 H), 7.45 (dm, J = 9.0 Hz, 2 H), 7.95 (br s, 1 H).
13C NMR (75.5 MHz, CDCl3): δ = 22.0, 22.1, 22.9, 23.8 (t,
3
3JCF = 5.4 Hz), 23.9, 24.1 (t, JCF = 5.1 Hz), 26.5, 26.7, 29.1 (t,
2JCF = 23.1 Hz), 29.4 (t, 2JCF = 20.4 Hz), 29.6, 29.6, 30.1, 30.7, 31.6,
13C NMR (75.5 MHz, CDCl3): δ = 14.6, 24.7 (t, 3JCF = 4.9 Hz), 32.5
2
1
31.6, 37.8, 37.9, 39.7, 39.8, 41.8, 42.0, 50.4, 50.4, 55.9, 55.9, 56.7,
(t, JCF = 23.7 Hz), 55.7, 60.7, 114.5, 117.9 (t, JCF = 254.2 Hz),
1
1
122.4, 122.8, 129.2, 146.1, 157.5, 161.8 (t, 2JCF = 28.4 Hz), 166.5.
57.1, 75.1, 75.2, 112.6 (t, JCF = 244.3 Hz), 114.6 (t, JCF = 247.2
Hz), 115.2, 115.2, 125.3, 125.4, 125.5, 125.6, 128.2, 128.3, 129.7,
129.8, 131.5, 131.6, 152.0, 152.2, 159.5, 159.6, 162.2 (t, 3JCF = 29.8
Hz), 162.3 (t, 2JCF = 30.2 Hz), 169.7, 169.8.
3
19F NMR (282.4 MHz, CDCl3): δ = –106.13 (dt, JHF = 16.3 Hz,
4JHF = 2.5 Hz, 2 F).
HRMS (ESI): m/z [M + Na]+ calcd for C15H17F2NNaO4: 336.1023;
found: 336.1024.
19F NMR (282.4 MHz, CDCl3): δ (major) = –100.2 (dt, 2JCF = 281.1
Hz, 3JHF = 16.1 Hz, 1 F), –101.8 (ddd, 2JCF = 281.1 Hz, 3JCF = 17.4
Hz, 1 F); δ (minor) = –100.5 (dt, 2JCF = 281.1 Hz, 3JHF = 15.0 Hz, 1
F), –101.7 (dt, 2JCF = 281.7 Hz, 3JHF = 19.6 Hz, 1 F).
Synthesis 2012, 44, 1863–1873
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Tandem Reaction for the Synthesis of α,α-Difluorinated Lactams
1871
Ethyl (2E)-5,5-Difluoro-6-(methoxyamino)-6-oxohex-2-enoate
1H NMR (300 MHz, CDCl3): δ = 1.27 (t, 3J = 7.2 Hz, 3 H), 1.57–
(5b)
1.64 (m, 1 H), 1.83–1.89 (m, 2 H), 1.95–2.03 (m, 2 H), 2.20–2.30
(m, 2 H), 2.38–2.43 (m, 2 H), 2.84 (q, J = 8.4 Hz, 1 H), 3.08–3.14
(m, 1 H), 3.31 (s, 3 H), 3.37–3.48 (m, 2 H), 4.17 (q, J = 7.2 Hz, 2
H), 5.84 (dt, 3J = 16.0 Hz, 4J = 1.5 Hz, 1 H), 6.91 (dt, J = 15.6 Hz,
J = 7.0 Hz, 1 H), 7.53 (br s, 1 H).
13C NMR (75.5 MHz, CDCl3): δ = 14.4, 21.4, 24.5 (t, 3JCF = 4.8 Hz),
26.1, 32.6 (t, 2JCF = 23.4 Hz), 55.4, 59.3, 60.5, 64.3, 75.3, 117.9 (t,
1JCF = 253.5 Hz), 122.7, 146.0, 162.2 (t, 2JCF = 24.8 Hz), 166.4.
Brown oil; yield: 64 mg (71%).
3
1H NMR (300 MHz, CDCl3): δ = 1.28 (t, J = 6.9 Hz, 3 H), 3.03
(tdd, 3JHF = 33.6 Hz, 3JHF = 16.8 Hz, 3J = 1.2 Hz, 2 H), 3.81 (s, 3 H),
4.19 (dd, 2J = 12.3 Hz, 3J = 7.2 Hz, 2 H), 6.01 (d, 3J = 15.9 Hz, 1 H),
6.80 (quint, 1 H), 9.26 (br s, 1 H).
2
13C NMR (75.5 MHz, CDCl3): δ = 14.6, 37.0 (t, JCF = 24.5 Hz),
1
3
61.1, 65.0, 116.9 (t, JCF = 255.9 Hz), 128.0, 136.7 (t, JCF = 5.3
Hz), 160.8 (t, 2JCF = 27.9 Hz), 165.9.
2
19F NMR (282.4 MHz, CDCl3): δ = –106.7 (dt, JFF = 259.8 Hz,
3JHF = 16.7 Hz, 1 F), –107.6 (dt, 2JFF = 258.8 Hz, 3JHF = 16.4 Hz, 1
19F NMR (282.4 MHz, CDCl3): δ = –106.4 (t, 3JHF = 16.7 Hz, 2 F).
HRMS (EI): m/z [M + Na]+ calcd C9H13F2NNaO4: 260.0710; found:
F).
HMRS (ESI): m/z [M + H+] calcd for C15H25F2NO4: 335.1777;
found: 335.1758.
260.0717.
Ethyl (2E)-6,6-Difluoro-7-[(4-methoxyphenyl)amino]-7-oxo-
hept-2-enoate (5c)
(1R,2S,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)cyclohexyl
(2E)-5,5-Difluoro-6-[(4-methoxyphenyl)amino]-6-oxohex-2-
enoate (5g)
Brown solid; yield: 111 mg (89%); mp 67–70 °C.
1H NMR (300 MHz, CDCl3): δ = 1.26 (t, 3J = 6.9 Hz, 3 H), 2.36 (m,
Brown oil; yield: 165 mg (87%); [α]D25 +49.9 (c 1.0, CHCl3).
4 H), 3.78 (s, 3 H), 4.16 (dd, 2J = 14.1 Hz, 3J = 7.2 Hz, 2 H), 5.85
1H NMR (300 MHz, CDCl3): δ = 0.88 (d, 3J = 6.6 Hz, 3 H), 0.96 (t,
J = 12.0 Hz, 1 H), 1.04–1.16 (m, 1 H), 1.22 (s, 3 H), 1.29 (s, 3 H),
1.42–1.58 (m, 1 H) 1.64–1.79 (m, 2 H), 1.86–1.93 (m, 1 H), 2.07
(ddd, J = 22.7 Hz, J = 10.5 Hz, J = 3.6 Hz, 1 H), 2.97 (tdd,
3JHF = 33.8 Hz, J = 7.2 Hz, J = 1.2 Hz, 2 H), 3.82 (m, 3 H), 4.11–
4.19 (m, 1 H), 4.86 (td, J = 21.4 Hz, J = 4.2 Hz, 1 H), 5.43 (d,
3J = 15.6 Hz, 1 H), 6.45 (dt, 3J = 15.6 Hz, 3J = 7.5 Hz, 1 H), 6.87–
6.94 (m, 2 H), 7.09–7.18 (m, 1 H), 7.22–7.28 (m, 4 H), 7.46–7.51
(m, 2 H), 7.94 (br s, 1 H).
13C NMR (75.5 MHz, CDCl3): δ = 22.2, 24.9, 26.9, 28.6, 31.7, 34.5,
36.9 (t, 2JCF = 24.5 Hz), 39.9, 41.9, 50.8, 55.7, 74.9, 114.7, 116.9 (t,
1JCF = 255.7 Hz), 122.5, 125.2, 127.7, 128.2, 128.3, 129.1, 135.8 (t,
3JCF = 4.9 Hz), 151.9, 157.7, 161.3 (t, 2JCF = 27.8 Hz), 164.9.
3
(dt, 3J = 15.9 Hz, J = 1.5 Hz, 1 H), 6.90 (m, 3 H), 7.46 (3J = 15.9
Hz, 4J = 9.3 Hz, 5J = 4.5 Hz, 2 H), 8.06 (br s, 1 H).
13C NMR (75.5 MHz, CDCl3): δ = 14.6, 24.7 (t, 3JCF = 4.9 Hz), 32.5
2
1
(t, JCF = 23.7 Hz), 55.7, 60.7, 114.5, 117.9 (t, JCF = 254.2 Hz),
122.4, 122.8, 129.2, 146.1, 157.5, 161.8 (t, 2JCF = 28.4 Hz), 166.5.
3
19F NMR (282.4 MHz, CDCl3): δ = –106.13 (dt, JHF = 16.3 Hz,
4JHF = 2.5 Hz, 2 F).
HRMS (EI): m/z [M]+ calcd C16H19F2NO4: 327.1282; found:
327.1291.
Ethyl (2E)-6,6-Difluoro-7-(methoxyamino)-7-oxohept-2-enoate
(5d)
Brown oil; yield: 72 mg (75%).
3
19F NMR (282.4 MHz, CDCl3): δ = –105.1 (dt, JHF = 33.8 Hz,
1H NMR (300 MHz, CDCl3): δ = 1.25 (t, 3J = 7.2 Hz, 3 H), 2.17–
2.47 (m, 4 H), 3.79 (s, 3 H), 4.16 (dd, 2JHF = 14.4 Hz, 3JHF = 7.2 Hz,
2 H), 5.84 (dt, 2J = 15.6 Hz, 3J = 1.5 Hz, 1 H), 6.89 (td, 3J = 15.7 Hz,
3J = 6.6 Hz, 1 H), 9.76 (br s, 1 H).
4JHF = 2.8 Hz, 2 F).
HRMS (ESI): m/z [M + Na]+ calcd for C29H35F2NNaO4: 522.2429;
found: 522.2426.
13C NMR (75.5 MHz, CDCl3): δ = 14.5, 24.5 (t, 3JCF = 4.9 Hz), 32.2
(1R,2S,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)cyclohexyl
(2E)-6,6-Difluoro-7-[(4-methoxyphenyl)amino]-7-oxohept-2-
enoate (5h)
2
1
(t, JCF = 23.3 Hz), 60.8, 64.8, 117.8 (t, JCF = 253.3 Hz), 122.9,
146.0, 161.4 (t, 2JCF = 28.6 Hz), 166.7.
Brown oil; yield: 174 mg (89%); [α]D25 +12.8 (c 1.0, CHCl3).
19F NMR (282.4 MHz, CDCl3): δ = –107.4 (t, 3JHF = 16.3 Hz, 2 F).
HRMS (ESI): m/z [M + H]+ calcd for C10H16F2NO4: 252.1030;
1H NMR (300 MHz, CDCl3): δ = 0.86 (d, 3J = 6.3 Hz, 3 H), 0.96 (t,
J = 12.3 Hz, 1 H), 1.06–1.14 (m, 1 H), 1.19 (s, 3 H), 1.28 (s, 3 H),
1.62–1.77 (m, 2 H) 1.83–1.91 (m, 2 H), 2.01–2.09 (m, 1 H), 2.27–
2.31 (m, 2 H), 3.74 (t, J = 6.6 Hz, 1 H), 3.80 (s, 3 H), 4.82 (ddd,
J = 21.3 Hz, J = 10.8 Hz, J = 4.2 Hz, 1 H), 5.57 (d, 3J = 15.9 Hz, 1
found: 252.1037.
Ethyl (2E)-5,5-Difluoro-6-{[(2S)-2-(methoxymethyl)pyrrolidin-
1-yl]amino}-6-oxohex-2-enoate (5e)
3
3
Yellow oil; yield: 91 mg (75%); [α]D25 –15.0 (c 1.0, CHCl3).
H), 6.39 (dt, J = 15.3 Hz, J = 6.0 Hz, 1 H), 6.87–6.91 (m, 2 H),
7.06–7.15 (m, 1 H), 7.22–7.25 (m, 2 H), 7.25–7.26 (m, 1 H), 7.45–
7.55 (m, 4 H), 7.69–7.74 (m, 1 H), 7.96 (br s, 1 H).
1H NMR (300 MHz, CDCl3): δ = 1.26 (t, 3J = 7.1 Hz, 3 H), 1.57–
1.68 (m, 1 H), 1.81–2.05 (m, 3 H), 2.82 (q, J = 8.5 Hz, 1 H), 3.00
(td, J = 16.7 Hz, J = 7.4 Hz, J = 1.3 Hz, 2 H), 3.08–3.13 (m, 1 H),
3.21–3.30 (m, 1 H), 3.31 (s, 3 H), 3.37–3.46 (m, 2 H), 4.17 (q, J =
7.2 Hz, 2 H), 5.98 (d, 3J = 15.7 Hz, 1 H), 6.81 (dt, 3J = 15.7 Hz, J =
7.2 Hz, 1 H), 7.61 (br s, 1 H).
13C NMR (75.5 MHz, CDCl3): δ = 22.2, 24.5 (t, 3JCF = 4.9 Hz), 24.9,
26.9, 28.6, 31.7, 32.5 (t, 2JCF = 23.5 Hz), 34.9, 39.9, 42.9, 50.8, 55.8,
74.7, 114.7, 118.1 (t, 1JCF = 253.8 Hz), 122.3, 125.1, 125.7, 128.3,
129.2, 129.3, 132.6, 152.1, 157.7, 161.7 (t, 2JCF = 28.2 Hz), 165.7.
19F NMR (282.4 MHz, CDCl3): δ = –106.1 (t, 3JHF = 16.3 Hz, 2 F).
HRMS (ESI): m/z [M + H]+ calcd for C30H38F2NO4: 514.2763;
13C NMR (75.5 MHz, CDCl3): δ = 14.2, 21.1, 25.9, 36.8 (t, 2JCF
=
1
24.5 Hz), 55.2, 59.1, 60.6, 64.1, 74.7, 116.5 (t, JCF = 255.2 Hz),
127.4, 136.4 (t, 3JCF = 5.3 Hz), 161.6 (t, 2JCF = 21.1 Hz), 165.4.
found: 514.2755.
19F NMR (282.4 MHz, CDCl3): δ = –106.2 (dt, 4JHF = 5.1 Hz, 3JHF
=
(1R,2S,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)cyclohexyl
(2E)-5,5-Difluoro-6-(methoxyamino)-6-oxohex-2-enoate (5i)
Brown oil; yield: 74 mg (46%); [α]D25 +4.3 (c 1.0, CHCl3).
16.7 Hz, 2 F).
HMRS (ESI): m/z [M + H+] calcd for C14H23F2N2O4: 321.1538;
found: 321.1534.
1H NMR (300 MHz, CDCl3): δ = 0.87 (d, 3J = 6.6 Hz, 3 H), 0.89–
1.01 (m, 1 H), 1.10 (td, J = 12.6 Hz, J = 3.3 Hz, 1 H), 1.18–1.28 (m,
1 H), 1.19 (s, 3 H), 1.28 (s, 3 H), 1.34–1.53 (m, 1 H), 1.63–1.78 (m,
2 H), 1.85–1.92 (m, 1 H), 2.01–2.06 (m, 1 H), 2.87 (dtd, J = 7.4 Hz,
J = 16.9 Hz, J = 1.3 Hz, 2 H), 3.82 (s, 3 H), 4.83 (td, J = 10.7 Hz,
J = 4.5 Hz, 1 H), 5.37 (d, J = 15.7 Hz, 1 H), 6.36 (dt, 3J = 15.6 Hz,
Ethyl (2E)-6,6-Difluoro-7-[(2S)-2-(methoxymethyl)pyrrolidin-
1-yl]amino}-7-oxohex-2-enoate (5f)
Yellow oil; yield: 81 mg (64%); [α]D25 –15.8 (c 1.0, CHCl3).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1863–1873

1872
S. Fustero et al.
SPECIAL TOPIC
3J = 5.7 Hz, 1 H), 7.08–7.15 (m, 1 H), 7.18–7.29 (m, 4 H), 9.03 (br
s, 1 H).
Acknowledgment
We would like to thank MICINN (CTQ2010-19774) of Spain and
Generalitat Valenciana (PROMETEO/2010/061) for their financial
support. C.B. expresses her thanks to Generalitat Valenciana for a
predoctoral fellowship.
13C NMR (75.5 MHz, CDCl3): δ = 22.1, 24.9, 26.9, 28.6, 31.7, 34.9,
36.9 (t, 2JCF = 24.0 Hz), 39.9, 41.9, 50.9, 65.0, 75.1, 116.8, 117.7 (t,
1JCF = 266.4 Hz), 122.7, 125.2, 125.4, 125.7, 128.3, 135.4 (t,
3JCF = 10.3 Hz), 151.9, 160.9 (t, 2JCF = 28.4 Hz), 165.0.
19F NMR (282.4 MHz, CDCl3): δ = –106.4 (d, J = 8.5 Hz, 2 F).
HRMS (ESI): m/z [M + NH4]+ calcd for C23H35F2N2O4: 441.2559;
References
found: 441.2558.
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Alvarado, P.; Giorgi, G.; Menéndez, J. C. Chem. Soc. Rev.
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(b) Krishna, P. R.; Sreeshailam, A.; Srinivas, R.
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Hsu, C.-S.; Liao, J.-H.; Lee, G.-H. Org. Lett. 2011, 13, 1338.
(b) Fustero, S.; Moscardó, J.; Sánchez-Roselló, M.; Flores,
S.; Guerola, M.; del Pozo, C. Tetrahedron 2011, 67, 7412.
(c) Bandini, M.; Eichholzer, A.; Tragni, M.; Umani-Ronchi,
A. Angew. Chem. Int. Ed. 2008, 47, 3238. (d) Rolfe, A.;
Young, K.; Hanson, P. R. Eur. J. Org. Chem. 2008, 5254.
(e) Fustero, S.; Jiménez, D.; Moscardó, J.; Catalán, S.; del
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J.; Sánchez-Roselló, M.; Rodríguez, E.; Barrio, P. Org. Lett.
2010, 12, 5494. (g) Fustero, S.; Rodríguez, E.; Herrera, L.;
Asensio, A.; Maestro, M. A.; Barrio, P. Org. Lett. 2011, 13,
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Chan, L. K. M. Org. Biomol. Chem. 2012, 10, 1322.
(b) Kotha, S.; Dipak, M. K. Tetrahedron 2012, 68, 397.
(c) Prunet, J. Eur. J. Org. Chem. 2011, 3634. (d) Nolan, S.
P.; Clavier, H. Chem. Soc. Rev. 2010, 39, 3305.
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Hoveyda, A. H. Nature (London) 2011, 471, 461.
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Chem. Rev. 2001, 69, 1001.
(1R,2S,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)cyclohexyl
(2E)-6,6-Difluoro-7-(methoxyamino)-7-oxohept-2-enoate (5j)
Brown oil; yield: 66 mg (38%); [α]D25 +19.3 (c 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 0.84 (d, 3J = 6.6 Hz, 3 H), 0.87–
0.99 (m, 2 H), 1.07 (td, J = 12.8 Hz, J = 3.0 Hz, 1 H), 1.17 (s, 3 H),
1.26 (s, 3 H), 1.59–1.74 (m, 3 H), 1.83–1.89 (m, 1 H), 1.99–2.17 (m,
3 H), 2.19–2.28 (m, 2 H), 3.71 (s, 3 H), 4.79 (td, J = 10.8 Hz, J = 4.2
Hz, 1 H), 5.23 (dt, J = 17.1 Hz, J = 1.5 Hz, 1 H), 5.75 (br s, 1 H),
6.36 (dt, 3J = 15.8 Hz, 3J = 6.0 Hz, 1 H), 7.05–7.13 (m, 1 H), 7.18–
7.25 (m, 4 H).
13C NMR (75.5 MHz, CDCl3): δ = 22.2, 24.4 (t, 3JCF = 4.9 Hz), 24.9,
26.9, 28.7, 31.7, 32.4 (t, 2JCF = 23.3 Hz), 35.0, 40.0, 42.1, 50.9, 74.7,
117.7 (t, 1JCF = 257.4 Hz), 123.1, 125.2, 125.4, 125.7, 125.8, 128.3,
128.4, 142.2, 152.2, 160.2 (t, 2JCF = 27.1 Hz), 165.7.
19F NMR (282.4 MHz, CDCl3): δ = –107.4 (t, J = 16.1 Hz, 2 F).
HRMS (ESI): m/z [M + NH4]+ calcd for C23H35F2N2O4: 441.2565;
found: 441.2558.
(1R,2S,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)cyclohexyl
(4,4-Difluoro-5-oxopyrrolidin-2-yl)acetate (6)
A soln of CAN (8 mmol) in H2O (2 mL) was added dropwise to a
soln of ester 3m (40 mg, 0.08 mmol; 83:17 mixture of diastereoiso-
mers) in MeCN (2 mL) at 0 °C. The ice bath was removed and the
mixture was stirred for 5 d at r.t. until the starting material was con-
sumed (TLC). 3 M aq HCl (5 mL) was then added and the mixture
was stirred for 1 h to give a yellow soln. The soln was basified with
sat. aq NaHCO3 until it became almost transparent then extracted
with EtOAc (4 × 10 mL). The combined organic layers were
washed with 20% aq Na2SO3 (10 mL), dried (Na2SO4), and concen-
trated under reduced pressure. The crude mixture was purified by
flash column chromatography [hexanes–EtOAc (1:1)] to give a
slightly yellow oil: yield: 17 mg (54%; 83:17 mixture of diastereo-
isomers).
1H NMR (300 MHz, CDCl3): δ = 0.83–0.99 (m, 6 H), 1.13 (s, 3 H),
1.14–1.22 (m, 2 H), 1.25 (s, 3 H), 1.47 (dd, J = 17.1 Hz, J = 10.8
Hz, 2 H), 1.66–1.79 (m, 3 H), 1.82–1.96 (m, 3 H), 2.03–2.11 (m, 1
H), 2.46–2.63 (m, 1 H), 3.47–3.58 (m, 1 H), 4.83 (td, J = 21.3 Hz,
J = 10.5 Hz, J = 4.5 Hz, 1 H), 6.45 (br s, 1 H), 7.04–7.11 (m, 1 H),
7.14–7.20 (m, 1 H), 7.23–7.25 (m, 4 H).
(8) (a) Alcaide, B.; Almendros, P.; Luna, A. Chem. Rev. 2009,
109, 3817. (b) Alcaide, B.; Almendros, P. Chem.–Eur. J.
2003, 9, 1259.
(9) Kwon, S.-H.; Lee, H.-J.; Cho, C.-W. Bull. Korean Chem.
Soc. 2011, 32, 315.
(10) Cai, C.; Zheng, C.; You, S.-L. Angew. Chem. Int. Ed. 2010,
49, 8666.
(11) Fustero, S.; Jiménez, D.; Sánchez-Roselló, M.; del Pozo, C.
J. Am. Chem. Soc. 2007, 129, 6700.
(12) Fustero, S.; Monteagudo, S.; Sánchez-Roselló, M.; Flores,
S.; Barrio, P.; del Pozo, C. Chem.–Eur. J. 2010, 16, 9835.
(13) For representative examples, see: (a) Surmont, R.; Verniest,
G.; Thuring, J. W.; Macdonald, G.; Deroose, F.; De Kimpe,
N. J. Org. Chem. 2010, 75, 929. (b) Qiu, X.-L.; Meng, W.-
D.; Qing, F.-L. Tetrahedron 2004, 60, 5201. (c) Osipov, S.
N.; Tsouker, P.; Hennig, L.; Burger, K. Tetrahedron 2004,
60, 271. (d) Qiu, X.-L.; Qing, F.-L. J. Org. Chem. 2003, 68,
3614. (e) Qiu, X.-L.; Qing, F.-L. J. Org. Chem. 2002, 67,
7162. (f) Macdonald, S. J. F.; Inglis, G. G. A.; Bentley, D.;
13C NMR (75.5 MHz, CDCl3): δ (first isomer) = 22.2, 26.5, 31.7,
2
318, 34.8, 36.7 (t, JCF = 22.7 Hz), 39.7, 40.4, 42.2, 44.9 (t,
3JCF = 3.6 Hz), 50.3, 75.3, 117.1 (t, 1JCF = 250.7 Hz), 125.5, 125.7,
128.4, 128.5, 152.4, 165.2 (t, 3JCF = 31.0 Hz), 170.1; δ (second iso-
2
mer) = 22.4, 27.4, 30.9, 31.6, 34.8, 35.6, 36.8 (t, JCF = 21.9 Hz),
3
39.7, 40.3, 42.1, 44.9 (t, JCF = 3.6 Hz), 50.4, 75.1, 122.0 (t,
1JCF = 251.8 Hz), 125.6, 125.7, 128.1, 128.2, 152.6, 165.1 (t,
3JCF = 29.2 Hz), 168.9.
19F NMR (282.4 MHz, CDCl3): δ (first isomer) = –104.3 (dtt,
3
4
2JFF = 272.8 Hz, JHF = 28.2 Hz, JHF = 3.1 Hz, 1 F), –107.5 (ddd,
2JFF = 272.5 Hz, 3JHF = 15.3 Hz, 4JHF = 2.5 Hz, 1 F); δ (second iso-
mer) = –105.2 (dtt, 2JFF = 271.4 Hz, 3JHF = 29.1 Hz, 4JHF = 3.1 Hz,
1 F), –107.6 (ddd, 2JFF = 271.5 Hz, 3JHF = 16.2 Hz, 4JHF = 2.3 Hz, 1
F).
HRMS (ESI): m/z [M + H]+ calcd for C22H30F2NO3: 394.2188;
found: 394.2190.
Synthesis 2012, 44, 1863–1873
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Tandem Reaction for the Synthesis of α,α-Difluorinated Lactams
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1863–1873