Concise preparation of 2,2-difluorohomopropargyl carbonyl derivatives. Application to the synthesis of 4,4-difluoroisoquinolinone congeners

Article abstract of DOI:10.1021/jo7025965

(Chemical Equation Presented) A scalable synthesis of 2,2- difluorohomopropargyl esters was achieved using a magnesium-promoted Barbier reaction of substituted difluoropropargyl bromides with alkyl chloroformates. These 2,2-difluorohomopropargyl esters we

Full text of DOI:10.1021/jo7025965

Concise Preparation of 2,2-Difluorohomopropargyl Carbonyl
Derivatives. Application to the Synthesis of
4,4-Difluoroisoquinolinone Congeners
Satoru Arimitsu,† Begon˜a Ferna´ndez,‡ Carlos del Pozo,‡ Santos Fustero,*,‡,§ and
Gerald B. Hammond*,†
Department of Chemistry, UniVersity of LouisVille, LouisVille, Kentucky 40292, Departamento de Qu´ımica
Orga´nica, UniVersidad de Valencia, E-46100 Burjassot, Spain, and Laboratorio de Mole´culas Orga´nicas,
Centro de InVestigacio´n Pr´ıncipe Felipe, E-46013 Valencia, Spain
gb.hammond@louisVille.edu; santos.fustero@uV.es
ReceiVed December 4, 2007
A scalable synthesis of 2,2-difluorohomopropargyl esters was achieved using a magnesium-promoted
Barbier reaction of substituted difluoropropargyl bromides with alkyl chloroformates. These 2,2-
difluorohomopropargyl esters were effective precursors in the synthesis of homopropargylic amidessby
aminolysis using AlMe3, as well as of ketonessthrough the reaction of the corresponding Weinreb amides
with Grignard reagents. Ring closing metathesis using difluorinated 1,7-enyne carbonyl compounds
furnished six-membered diene products, which were used as susbstrates in a Diels-Alder reaction to
afford 4,4-difluoroisoquinolin-3-ones. The [2 + 2 + 2] cycloaddition of alkynes with fluorinated 1,7-
diyne amides gave 4,4-difluoro-1,4-dihydro-3(2H)-isoquinolinone derivatives regioselectively.
Introduction
similar efforts toward cyclic fluorinated structures are lacking.
New synthetic options for the synthesis of R,R-difluorometh-
ylene carbonyl compoundssespecially cyclic derivativessare
needed. One possible approach would be the transition-metal-
catalyzed cyclization of a suitably fluorinated carbonyl-contain-
ing unsaturated building block. In hydrocarbon chemistry, this
has become an important synthetic tool in modern organic
chemistry, because enables useful transformations employing
less steps than traditional methodologies.3 The fact that this
strategy has not received the attention it deserves may be due
The coming of age of fluorine is unquestionable after decades
of continuously impacting society. In particular, R,R-difluo-
romethylene carbonyl compounds have become increasingly
important in medicinal chemistry.1 Traditionally, fluorine has
been installed in these systems by a selective fluorination of an
R-ketocarbonyl group using diethylaminosulfur trifluoride (DAST)
or a double fluorination of the active R-methylene protons of
carbonyls; however, these fluorinating reagents are highly
reactive and do not tolerate a variety of substituents or reaction
conditions. The use of fluorine-containing unsaturated systems
in biological structures has been disclosed by several groups;2
(2) (a) You, Z.-W.; Jiang, Z.-X.; Wang, B.-L.; Qing, F.-L. J. Org. Chem.
2006, 71, 7261-7267. (b) Audouard, C.; Barsukov, I.; Fawcett, J.; Griffith,
G. A.; Percy, J. M.; Pintat, S.; Smith, C. A. Chem. Commun. 2004, 1526-
1527. (c) Hanzawa, Y.; Inazawa, K.; Kon, A.; Aoki, H.; Kobayashi, Y.
Tetrahedron Lett. 1987, 28, 659-662.
(3) (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. ReV. 2004, 104,
3079-3159. (b) Aubert, C.; Buisine, O.; Malacria, M. Chem. ReV. 2000,
102, 813-834. (c) Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Khan, F. A.
Chem. ReV. 2000, 100, 3067-3125. (d) Mu¨ller, T. E.; Beller, M. Chem.
ReV. 1998, 98, 675-703. (e) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan,
R. J. Chem. ReV. 1996, 96, 635-662. (f) Nakamura, I.; Yamamoto, Y.;
Chem. ReV. 1995, 104, 2127-2198.
* Corresponding author. Tel: +1-502-852-5998. Fax: +1-502-852-3899.
† University of Louisville.
‡ Universidad de Valencia.
§ Centro de Investigacio´n Pr´ıncipe Felipe.
(1) For reviews, see: (a) Uneyama, K. Organofluorine Chemistry;
Blackwell: Oxford 2006. (b) Chambers, R. D. Fluorine in Organic
Chemistry; Blackwell: Oxford 2004 (c) Kirsch, P. Modern Fluoroorganic
Chemistry; Wiley-VCH: Weinheim 2004. (d) Tozer, M. J.; Herpin, T. F.
Tetrahedron 1996, 52, 8619-8683.
10.1021/jo7025965 CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/06/2008
2656
J. Org. Chem. 2008, 73, 2656-2661

Preparation of 2,2-Difluorohomopropargyl Carbonyl DeriVatiVes
TABLE 1. Synthesis of 2,2-Difluorohomopropargyl Esters 3
SCHEME 1. Complementary Synthetic Approaches toward
gem-Difluoro Heterocycles
to limitations in the availability of starting materials bearing
fluorinated carbons next to unsaturated bonds, especially triple
bonds. A recent report by Bertozzi and co-workers4 has
highlighted the importance of cyclic gem-difluorodifluoropro-
pargyl systems in the study of copper-free cellular click
chemistry. Their paper also underscores the difficulty of
preparing cyclic fluorinated derivatives, as it took the Bertozzi
group 11 steps to synthesize their gem-difluorocyclooctyne
target.
We have recently begun to utilize the fluorinated triple bond
scaffold in cyclizations. As shown in Scheme 1, our group
possesses two complementary fluorinated starting materials. One
is equipped with a gem-difluorinated allenyl moiety, whereas
the other is fitted with a gem-difluorinated propargyl moiety.
The activation of X-H (X ) N, O) usually requires stoichio-
metric amounts of base (Scheme 1),5 but when we investigated
the use of catalytic amounts of transition metal for the efficient
activation of these fluorinated unsaturated bonds we obtained
unique gem-difluorocyclic structures.6
TABLE 2. Aminolysis of Esters 3 with Amines and AlMe3
In this paper, we are pleased to report the concise and scalable
synthesis of 2,2-difluorohomopropargyl compounds (esters,
amides and ketones) and their useful role of cyclization partners,
as demonstrated by novel syntheses of 4,4-difluoroisoquinoli-
none congeners.
Results and Discussion
Kobayashi has reported two procedures to prepare 2,2-
difluorohomopropargyl esters: the fluorination of homoprop-
argyl ketoester by DAST7 and the reaction of iododifluoroacetate-
copper with alkynyl iodide.8 However, both methods have
limitations on the scale-up and yields. To address these
shortcomings, we first examined the synthesis of 2,2-difluoro-
homopropargylic esters because esters can be readily converted
into other carbonyl analogs like amides and ketones.9 Optimized
reaction conditions10 were applied to the reaction of substituted
difluoropropargyl bromides 1 and alkyl chloroformates 2 (Table
a 2.0 equiv of amine and AlMe3 were used; the reaction time was 20 h.
b 1.05 equiv of 4d and AlMe3 were used; the reaction time was 1 h.
1, entries 1-8). These reactions were easily performed at a
molar fraction scale, and products were isolable by distillation.
Next, the transformation of methyl 2,2-difluoropropargyl esters
3b-e to the corresponding amides 5 were explored (Table 2).
The reactions were successfully carried out with aminoaluminum
reagents generated from AlMe3 and either primary amines
(entries 1-4, Table 2), secondary amines (entries 5-8, Table
2), or MeONHMe‚HCl salt (entries 9 and 10, Table 2), in
moderate to good yields.
(4) Baskin, J. M.; Prescher, J. A.; Laughlin, S. T.; Agard, N. J.; Chang,
P. V.; Miller, I. A.; Lo, A.; Codelli, J. A.; Bertozzi, C. R. Proc. Nat. Acad.
Sci. U.S.A. 2007, 104, 16793-16797.
(5) (a) Lan, Y.; Hammond, G. B. Org. Lett. 2002, 4, 2437-2439. (b)
Wang, Z.; Hammond, G. B. J. Org. Chem. 2000, 65, 6547-6552. (c) Sham,
H. L.; Betebenner, D. A. J. Chem. Soc., Chem. Commun. 1991, 1134-
1135.
(6) (a) Arimitsu, S.; Hammond. G. B. J. Org. Chem. 2007, 72, 8559-
8561. (b) Shen, Q.; Hammond, G. B. J. Am. Chem. Soc. 2002, 124, 6534-
6535.
(7) Hanazawa, Y.; Kawagoe, K.; Inazawa, K.; Kobayashi, Y. Tetrahedron
Lett. 1988, 29, 5665-5666.
(8) Taguchi, T.; Kitagawa, O.; Morikawa, T.; Nishiwaki, T.; Uehara,
H.; Endo, H.; Kobayashi, Y. Tetrahedron Lett. 1986, 27, 6103-6106.
(9) Larock, R. C. ComprehensiVe Organic Transformations; Wiley-VCH
Publishers: New York 1989.
(10) Other solvents (Et2O and DMF) and temperatures (rt, -20 °C and
-78 °C) did not give satisfactory results.
The reaction of Weinreb amides and Grignard reagents gave
the best results in the preparation of 2,2-difluorohomopropargyl
ketones 7 (Table 3).11 Various Grignard reagents containing
(11) Other synthetic protocols attempted included (i) the reaction of 1
with acyl chloride in the presence of Mg and (ii) the reaction of 3 with
Grignard reagents. Both procedures resulted in no reaction or complex
mixtures.
J. Org. Chem, Vol. 73, No. 7, 2008 2657

Arimitsu et al.
SCHEME 2. Ruthenium Carbene Metathesis Complexes
TABLE 3. Synthesis of 2,2-Difluorohomopropargyl Ketones 7
TABLE 5. Screening Reaction Conditions for the Enyne
Metathesis of 8c
TABLE 4. Desilylation of TIPS
yields of
T
producta (%)
entry
solvent
toluene
toluene
toluene
toluene
1,2-dichloroethane
THF
toluene
toluene
Ru cat.
gas
(°C)
8c/9a/9a-iso
1
2
3
4
5
6
7
8
G-I
G-II
C2H4
C2H4
C2H4
C2H4
C2H4
C2H4
Argon
110
110
110
70
70
70
53/0/0
0/34/0
HG-II
HG-II
HG-II
HG-II
HG-II
HG-II
0/6/66 (60)b
0/85 (70)/0
no rxn
30/25/0
28/34/0
0/20/11
70
110
c
C2H4
a Yield was determined by 19F NMR, and the value in parentheses is the
isolated yield. b 9a-iso was isolated as an E/Z mixture (E/Z ) 3/1). c 20
mol % of 2,6-dichloro-1,4-benzoquinone was used.
SCHEME 3. Diels-Alder Reaction of Diene 9 with 11 and
13
aromatic substituents bearing electron-withdrawing (entry 3,
Table 3) and electron-donating groups (entries 4 and 5, Table
3), as well as an aliphatic substituent (entry 6, Table 3), gave
the desired ketones 7 in good yields.
The triisopropylsilyl (TIPS) substituent serves not only as a
useful synthetic handle but it is also a protective group on
reactive triple bonds.12 We found that desilylation could be
accomplished smoothly using TBAF and CH3CO2H without any
noticeable degradation (Table 4). These newly synthesized 2,2-
difluorohomopropargyl carbonyl derivatives are versatile mo-
lecular building blocks for the synthesis of gem-difluoro
heterocyclic compounds. For example, we recently reported the
use of amides 5c in the selective synthesis of â-lactamssusing
Pd(OAc)2 as a Lewis acidsand γ-lactamsswith TBAF as a
base.13
The gem-difluorocarbonyl substrates described above can be
used in the synthesis of heterobicyclic and -tricyclic systems.
First, we investigated the ring closing metathesis reaction of 8
with ruthenium carbene complexes, as the resulting diene
product could be elaborated further using a Diels-Alder reaction
(Scheme 3).14 During the course of screening this reaction, we
found the Hoveyda-Grubbs second-generation catalyst to be
the most reactive among other ruthenium carbene complexes
(Scheme 2, Table 5), but the reaction at 110 °C gave 9a-iso as
the major compound, probably through the isomerization of 9a15
(entry 3, Table 5). The latter was obtained when the reaction
was carried out at 70 °C in toluene (entry 4, Table 5). Other
solvents (e.g., 1,2-dichloroethane or THF) gave neither good
yields nor selectivities (entries 5 and 6, Table 5). From
experimentation, it became clear that ethylene gas was crucial
to make this reaction proceed forward (compare entry 4 with
7, Table 5).16a 2,6-Dichloro-1,4-benzoquinone, which has been
reported to prevent isomerization,16b gave disappointing results
(12) Ru¨cker, C. Chem. ReV. 1995, 95, 1009-1064.
(13) Fustero, S.; Ferna´ndez, B.; Bello, P.; del Pozo, C.; Arimitsu, S.;
Hammond, G. B. Org. Lett. 2007, 9, 4251-4253.
(15) For tandem RCM-isomerization reactions, see: Fustero, S.; Sa´nchez-
Rosello´, M.; Jime´nez, D.; Sanz-Cervera, J. F.; del Pozo, C.; Acen˜a, J. L. J.
Org. Chem. 2006, 71, 2706-2714 and literature cited therein.
(16) (a) Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998,
63, 6082-6083. (b) Hong, S. K.; Sanders, D. P.; Lee, C. W.; Grubbs, R.
H. J. Am. Chem. Soc. 2005, 127, 17160-17161.
(14) (a) M. Mori, M. Ene-yne Metathesis. In Handbook of Metathesis;
Grubbs, R. H., Eds.; Wiley-VCH: Weinheim, 2003; Vol. 2, p 176. (b) Diver,
S. T.; Giessert, A. J. Chem. ReV. 2004, 104, 1317-1382. (c) Poulsen, C.
S.; Madsen, R. Synthesis 2003, 1, 1-18.
2658 J. Org. Chem., Vol. 73, No. 7, 2008

Preparation of 2,2-Difluorohomopropargyl Carbonyl DeriVatiVes
TABLE 6. Metathesis Reaction of Fluorinated 1,7-Enyne Carbonyl
Compounds
TABLE 7. Synthesis of
4,4-Difluoro-1,4-dihydro-3(2H)-isoquinolinone Derivatives by [2 + 2
+ 2] Cycloaddition of 8d with Alkyne 15
entry
X
R
T (°C)
yields of 9a (%)
yields of product (%)
1
2
3
4
5
NBn
NBn
NBn
O
H (8c)
70
110
110
110
110
70 [85] (9a)
52 [78] (9b)
69 [95] (9c)
[33]b (9d)
entry
R1
R2
[16-I:16-II]a
n-Hex (5f)
Ph (5g)
Ph (3h)
Ph (7f)
1
2
3
4
5
6
7
8
CH2OH
TMS
C6H5
o-NO2C6H4
OEt
CO2Me
CH2OH
CO2Et
H (15a)
H (15b)
H (15c)
H (15d)
H (15e)
H (15f)
CH2OH (15g)
CO2Et (15h)
92 [1:4] (16a)
85 [1:3] (16b)
85 [1:6] (16c)
37 [1:1.5] (16d)
55 [1:2.5] (16e)
40 [1:2] (16f)
52 (16g)
C
[97]c (9e)
a The yields in brackets were determined by 19F NMR. b Isolation of 9d
was unsuccessful due to the complex mixture formed. c Compound 10 was
isolated in 84 % after silica gel chromatography.
45 (16h)
a The isomer ratio was determined by 19FNMR.
several alkynes 15 and catalytic amount of RhCl(PPh3)3 (5 mol
%) (Table 7). It is worth mentioning the interesting regiose-
lectivity of products 16-I/16-II observed when terminal alkynes
15a-f (entry 1-6, Table 7) were utilized. The product 16-II
was obtained as the major isomer in all cases regardless of the
substrate on the terminal alkyne 15. It is known that the
regioselectivity of [2 + 2 + 2] cycloaddition is often controlled
by steric interactions between the substituents in diynes and
alkynes. However, both triple bonds in diyne 8d are terminal;
therefore, the observed regioselectivity could be explained by
cooperative effects between electron-withdrawing effects of
fluorine and steric interactions between ligand and substrate on
alkyne 15 in its transition state.22
In conclusion, the Barbier reaction of substituted difluoro-
propargyl bromides 1 with Mg and alkyl chloroformates
provides 2,2-difluorohomopropargyl esters 3, and the aminolysis
of methyl 2,2-difluorohomopropargyl esters furnished the cor-
responding amides 5. 2,2-Difluorohomopropargyl ketones 7
were successfully obtained by the reaction of its Weinreb amide
precursor with a Grignard reagent. These 2,2-difluorohomopro-
pargyl carbonyl compounds proved to be good cycloaddition
partners. The enyne metathesis of fluorinated 1,7-enyne carbonyl
compounds using Hoveyda-Grubbs second generation catalyst
furnished the six-membered diene ring 9, which proved to be
an efficient diene in a Diels-Alder reaction to afford 4,4-
difluoroisoquinolin-3-one. Additionally, a fluorinated 1,7-diyne
amide was used in the regioselective synthesis of 4,4-difluoro-
1,4-dihydro-3(2H)-isoquinolinones using a [2 + 2 + 2] cy-
cloaddition protocol with RhCl(PPh3)3.
(entry 8, Table 5). When our optimized conditions were applied
to other fluorinated 1,7-enynes, we only could isolate the
corresponding lactams (entries 1-3, Table 6). Higher temper-
atures were required when internal alkynes were employed
(entries 2-5, Table 6), but the enyne ester 3h did not give
satisfactory results. Interestingly, although enyne ketone 7f gave
a good 19F NMR yield of the desired diene 9e [97%, δ: -103.99
ppm (s, 2F)], after workup and silica gel chromatography we
only obtained, in good yield, the o-fluorophenol 10. This
unexpected result could have positive synthetic repercusions as
the o-fluorophenol is a moiety that has attracted attention
elsewhere.17
With an efficient access to conjugated dienes 9, we were in
the position to prepare bi- or tricyclic systems, as demonstrated
in Scheme 3. Accordingly, dienes 9a and 9b were used in
Diels-Alder reactions with 11 and 13 to give 12 and 4,4-
difluoroisoquinolin-3-one derivatives 14, respectively, in excel-
lent yield and good stereoselectivity.18
Fluorinated diynes are useful building blocks,19 as shown in
our reported synthesis of 3,3-difluoroisochroman derivatives
using [2 + 2 + 2] cycloaddition.20 To extend our methodology
further, we used 1,7-diyne amide 8d (see entry 4, Table 4) to
synthesize 4,4-difluoro-1,4-dihydro-3(2H)-isoquinolinones, which
could be expected to have interesting bioactivities and/or become
useful intermediates.21 The reaction proceeded effectively with
(17) (a) Dabidden, D. R.; Cheng, K. F.; Aljabari, B.; Miller, E. J.; Pavlov,
V. A.; Al-Abed, Y. J. Med. Chem. 2007, 50, 1993-1997. (b) Mewshaw,
R. E.; Bowen, S. M.; Harris, H. A; Xu, Z. B.; Manas, E. S.; Cohn, S. T.
Bioorg. Med. Chem. Lett. 2007, 17, 902-906. (c) Mewshaw, R. E.; Edsall,
J. R. J.; Yang, C.; Manas, E. S.; Xu, Z, B.; Henderson, R. A.; Keith, J. C.
J.; Harris, H. A. J. Med. Chem. 2005, 48, 3953-3979.
(18) The other isomers of 14a and 14b were isolated in 8% and 20%
yield, respectively.
(19) Grotjahn, D. B. Transition Metal Alkyne Complexes: Transition
Metal-Catalyzed Cyclotrimerization. In ComprehensiVe Organometallic
Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Hegedus,
L. S., Vol. Ed.; Pergamon: Oxford, 1995; Vol. 12, p 741 and literature
cited in reference 3.
Experimental Section
Synthesis of Methyl 2,2-Difluoro-4-(triisopropylsilyl)-3-bu-
tynoate (3b). A suspension of Mg (0.25 mol) and I2 (2.5 mmol) in
dry THF (400 mL) was stirred under argon for 30 min at room
temperature until the solution become cloudy. Then a solution of
the corresponding difluoropropargyl bromide 1b (0.1 mol) and
methyl chloroformate 2a (0.5 mol) was slowly added at 0 °C, rinsing
with dry THF (100 mL). The reaction mixture was stirred for 3 h
and quenched with aqueous 10% HCl (30 mL) in ice. The organic
solvent was removed by rotary evaporation, the reaction mixture
(20) Arimitsu, S.; Hammond, G. B. J. Org. Chem. 2006, 71, 8865-
8868.
(21) (a) Zhang, Y.; Kindelin, P. J.; DeSchepper, D. J.; Zheng, C.;
Klumpp, D. A. Synthesis 2006, 11, 1775-1780. (b) Philippe, N.; Levacher,
V.; Dupas, G.; Que´guiner, G.; Bourguignon, J. Org. Lett. 2000, 2, 2185-
2187. (c) Gea´k, G.; Do´da, M.; Gyo¨rgy, L.; Hazai, L.; Sterk, L. J. Med.
Chem. 1977, 20, 1384-1388.
(22) (a) Yamamoto, Y.; Ishii, J.; Nishiyama, H.; Itoh, K. J. Am. Chem.
Soc. 2005, 127, 9625-9631. (b) Yamamoto, Y.; Kinpara, K.; Saigoku, T.;
Takagishi, H.; Okuda, S.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2005,
127, 605-613.
J. Org. Chem, Vol. 73, No. 7, 2008 2659

Arimitsu et al.
was extracted with Et2O (3 × 30 mL) and washed by aqueous
saturated sodium bisulfite and brine, and the combined organic
layers were dried over Na2SO4. After removal of the solvent, 3b
was isolated by distillation in 73% yield (21.2 g). 1H NMR (CDCl3)
δ: 1.10-1.16 (bs, 21H), 3.94 (s, 1H); 19F NMR (CDCl3) δ: -90.50
(s, 2F). 13C NMR (CDCl3) δ: 11.0, 18.5, 54.2, 95.2 (t, J ) 36.5
Hz), 95.3 (t, J ) 5.0 Hz), 103.7 (t, J ) 242.1 Hz), 162.2 (t, J )
34.6 Hz). IR (neat) cm-1: 2947, 2870, 2185, 1772, 1471. MS m/z:
271 (100), 107 (55), 79 (38). HRMS (EI): calcd for C14H24F2O2Si
(M+) 290.1513, found 290.1511.
(s, 2F). 13C NMR (CDCl3) δ: 26.8, 35.0, 78.0 (t, J ) 38.6 Hz),
91.3 (t, J ) 6.5 Hz), 107.8 (t, J ) 244.5 Hz), 116.0, 119.2, 128.6,
130.6, 132.3, 135.8, 195.0 (t, J ) 31.2 Hz). IR (neat) cm-1: 3082,
2923, 2234, 1755. MS m/z: 234 (17, M+), 213 (19), 151 (100),
105 (67). HRMS (FAB): calcd for C14H12F2O (M+) 234.0856,
found 235.0925 (M+ + H).
Synthesis of N-Allyl-N-benzyl-2,2-difluoro-3-butynamide (8c).
A solution of AcOH (37.2 mmol) and TBAF (28.6 mmol, 28.6
mL of 1.0 M solution in THF) in wet THF (100 mL) was stirred
at room temperature for 30 min, and then a THF solution (30 mL)
of 5e (13.0 mmol) was added slowly at room temperature and the
mixture stirred at room temperature for 3 h. After this time, it was
quenched with water and extracted with EtOAc (3 × 40 mL). The
organic layer was washed with brine and dried over Na2SO4. The
final product 8c was isolated in 98% (3.18 g) after silica gel column
Synthesis of N-Allyl-N-benzyl-2,2-difluoro-4-(triisopropylsi-
lyl)-3-butynamide (5e). To a solution of N-allyl-N-benzylamine
4b (40 mmol) in dry CH2Cl2 (50 mL) at 0 °C under argon was
added dropwise AlMe3 (40 mmol, 20 mL of 2.0 M solution in
hexanes). The ice bath was removed, and the light yellow solution
was allowed to stir at room temperature for 1 h, after which it was
recooled to 0 °C. Then a solution of 3b (20 mmol) in CH2Cl2 (25
mL) was added, followed by CH2Cl2 (25 mL) used to aid in the
rinsing. The reaction mixture was allowed to warm to room
temperature and then heated to reflux temperature. After the mixture
was heated for 20 h, the consumption of 3b was confirmed by GC.
The reaction was quenched by aqueous 10% HCl (100 mL) in ice
and then extracted by EtOAc (3 × 30 mL), and the organic layer
was washed with brine and dried over Na2SO4. Pure compound 5e
was obtained in 61% yield (4.95 g) after silica gel chromatography
using hexane/EtOAc (30/1) as eluent. 1H NMR (CDCl3) δ: 0.97-
1.02 (m, 21H), 3.84 (d, J ) 8.0 Hz, 1H), 3.98 (d, J ) 6.0 Hz, 1H),
4.556 (s) and 4.68 (s) for 2H, 5.03 (d, J ) 17.5 Hz) and 5.14 (d,
J ) 17.5 Hz) for 1H, 5.13 (d, J ) 10.0 Hz) and 5.22 (d, J ) 10.0
Hz) for 1H, 5.61-5.75 (m, 1H), 7.14-7.30 (m, 5H). 19F NMR
(CDCl3) δ: -85.20 (s) and -86.20 (s) for 2F. 13C NMR (CDCl3)
δ: 10.8, 18.3, 47.6, 47.9, 49.2, 50.4, 95.1 (t, J ) 36.0 Hz), 96.6,
95.8, 95.9 (t, J ) 36.5 Hz), 105.0, (t, J ) 241.8 Hz), 105.1 (t, J )
241.9 Hz), 118.3, 119.3, 127.4, 127.6, 127.9, 128.0, 128.7, 128.8,
131.0, 132.3, 135.3, 135.8, 161.0 (t, J ) 29.2 Hz), 161.3 (t, J )
30.2 Hz). IR (neat) cm-1: 2945, 2867, 2359, 1689. MS m/z: 405
(3, M+), 92 (80).
Synthesis of N-Methoxy-N-methyl-2,2-difluoro-4-(triisopro-
pylsilyl)-3-butynamide (5i). To a suspension of MeONHMe‚HCl
4d (1.05 mmol) in dry CH2Cl2 (2.5 mL) at 0 °C under argon was
added dropwise AlMe3 (1.05 mmol, 0.52 mL of 2.0 M solution in
hexanes). The ice bath was removed, and the solution was allowed
to stir at room temperature for 1 h. After recooling to 0 °C, a
solution of 3b (1.0 mmol) in CH2Cl2 (1.5 mL) was added, followed
by CH2Cl2 (1.0 mL) used to the aid in the rinsing. The reaction
mixture was kept at 0 °C for 1 h, after which it was quenched with
aqueous 10% HCl (10 mL) in ice and extracted with EtOAc (3 ×
15 mL). The organic layer was washed with brine and dried over
Na2SO4. Pure compound 5i was obtained in 65% (208 mg) after
silica gel chromatography using hexane/EtOAc (40/1) as eluent.
1H NMR (CDCl3) δ: 1.06-1.14 (bs, 21H), 3.23 (bs, 3H), 3.76 (s,
3H). 19F NMR (CDCl3) δ: -88.78 (s, 2F). 13C NMR (CDCl3) δ:
10.7, 18.6, 33.0, 61.5, 93.4, 95.7 (t, J ) 35.2 Hz), 104.5 (t, J )
240.9 Hz), 161.0 (t, J ) 29.8 Hz); IR (neat) cm-1: 3419, 2945,
2867, 1700, 1174. MS m/z: 239 (6, M+), 116 (18), 93 (11). HRMS
(FAB): calcd for C15H27F2NO2Si (M+) 319.1779, found 320.1857
(M++H)
1
chromatography using hexane/EtOAc (20/1) as eluent. H NMR
(CDCl3) δ: 3.04 (t, J ) 5.5 Hz) and 3.07 (t, J ) 5.5 Hz) for 1H,
3.92 (d, J ) 6.0 Hz) and 4.04 (d, J ) 5.5 Hz) for 2H, 4.63 (s) and
4.74 (s) for 2H, 5.11 (d, J ) 17.0 Hz) and 5.23 (d, J ) 17.5 Hz)
for 1H, 5.22 (d, J ) 10.0 Hz) and 5.31 (d, J ) 10.5 Hz) for 1H,
5.70-5.83 (m, 1H), 7.23-7.34 (m, 5H); 19F NMR (CDCl3) δ:
-86.36 (s) and -87.00 (s) for 2F. 13C NMR (CDCl3) δ: 47.9,
48.2, 49.0, 50.1, 73.8 (t, J ) 37.5 Hz), 73.9 (t, J ) 37.5 Hz), 79.5
(t, J ) 6.3 Hz), 79.7 (t, J ) 6.2 Hz), 105.9 (t, J ) 243.8 Hz),
118.4, 119.4, 127.3, 127.7, 127.9, 128.1, 128.71, 128.73, 130.8,
131.9, 135.0, 135.7, 160.3 (t, J ) 29.3 Hz), 160.6 (t, J ) 29.8 Hz).
IR (neat) cm-1: 3225, 3087, 3031, 2933, 2125, 1681, 1445. MS
m/z: 249 (13, M+), 161 (17), 134 (4), 92 (8). Anal. Calcd: C,
67.46; H, 5.26. Found: C, 66.99; H, 5.26.
Synthesis of 1-Benzyl-3,3-difluoro-4-vinyl-3,6-dihydropyridin-
2-one (9a). To a suspension of Hoveyda-Grubbs second-generation
catalyst (0.38 mmol) in toluene (170 mL) was added 8c (3.8 mmol)
with the aid of toluene (20 mL) at room temperature under argon.
The argon gas was replaced with ethylene gas, and the mixture
was stirred at 70 °C for 3 h. The reaction was quenched with water
and extracted with EtOAc (3 × 20 mL), and the organic layer was
washed with brine and dried over Na2SO4. The final product 9a
was isolated in 70% (663 mg) after silica gel column chromatog-
1
raphy using hexane/EtOAc (4/1) as eluent. H NMR (CDCl3) δ:
3.88-3.91 (m, 2H), 4.63 (s, 2H), 5.26 (d, J ) 11.0 Hz, 1H), 5.63
(d, J ) 17.5 Hz, 1H), 6.08 (s, 1H), 6.19 (dd, J ) 18.0, 11.5 Hz,
1H), 7.18-7.28 (m, 5H). 19F NMR (CDCl3) δ: -95.83 (s, 2F).
13C NMR (CDCl3) δ: 46.7, 49.8, 107.6 (t, J ) 237.1 Hz), 118.9,
127.0, 128.1, 128.2, 128.9, 129.1, 131.0 (t, J ) 24.2 Hz), 135.0,
160.2 (t, J ) 29.8 Hz). IR (CCl4) cm-1: 3032, 2940, 1674. MS
m/z: 249 (13, M+), 230 (45), 91 (100). HRMS (FAB): calcd for
C14H12F2O (M+) 249.0965, found 250.1033.
Synthesis of Diels-Alder Adduct 12. To a solution of 11 (0.48
mmol) in CH2Cl2 (0.2 mL) was added 9a (0.32 mmol) with the
aid of CH2Cl2 (0.8 mL) at room temperature under argon. The
reaction mixture was stirred at room temperature for 2 h. The
reaction was quenched with water and extracted with CH2Cl2
(3 × 15 mL), and the organic layer was washed with brine and
dried over Na2SO4. The final product 12 was isolated in 95% yield
(194 mg) after silica gel column chromatography using CH2Cl2/
1
EtOAc (100/1) as eluent. H NMR (CDCl3) δ: 3.30 (dt, J ) 2.5,
10.8 Hz, 1H), 4.06 (dd, J ) 6.0, 11.0 Hz, 1H), 4.26-4.32 (m, 2H),
4.50 (d, J ) 14.5 Hz, 1H), 4.87 (d, J ) 14.5 Hz, 1H), 4.94 (bs,
1H), 6.64 (bs, 1H), 7.28-7.49 (m, 10H). 19F NMR (CDCl3) δ:
Synthesis of 3,3-Difluoro-1-phenyloct-7-en-1-yn-4-one (7f). To
a solution of 5j (4.7 mmol) in dry THF (47 mL) at 0 °C under
argon was added dropwise 3-butenylmagnesium bromide 6e (9.4
mmol, 18.8 mL of 0.5 M solution in THF). The reaction mixture
was stirred at 0 °C for 1.5 h, quenched with aqueous 10% HCl (30
mL) in ice, and extracted with Et2O (3 × 20 mL). The organic
layer was then washed with brine and dried over Na2SO4. Pure
compound 7f was obtained in 72% (793 mg) after silica gel
-88.27 (d, J ) 287.6 Hz, 1F), -119.01 (d, J ) 287.6 Hz, 1F). 13
C
NMR (CDCl3) δ: 42.7, 48.0, 49.2, 51.2, 108.0 (dd, J ) 249.4,
250.1 Hz), 121.6 (t, J ) 11.3 Hz), 125.2, 127.5 (t, J ) 22.8 Hz),
128.37, 128.43, 128.6, 129.1, 129.3, 130.4, 134.6, 151.76, 151.83,
160.2 (t, J ) 30.4 Hz). IR (CCl4) cm-1: 3064, 2948, 2890, 1727,
1677. HRMS (FAB): calcd for C22H18F2N4O3 (M+) 424.1347,
found 424.1354.
1
chromatography using hexane/EtOAc (15/1) as eluent. H NMR
(CDCl3) δ: 2.47 (apparent q, J ) 7.0 Hz, 2H), 2.93 (t, J ) 7.3 Hz,
2H), 5.06 (d, J ) 10.0 Hz, 1H), 5.12 (d, J ) 17.0 Hz, 1H), 5.81-
5.89 (m, 1H), 7.39-7.56 (m, 5H). 19F NMR (CDCl3) δ: -94.18
General Synthesis of 4,4-Difluoro-1,4-dihydro-3(2H)-isoquin-
olinone Derivatives (16). To a solution of the amide 8d (0.4 mmol)
in dry toluene (4 mL) at room temperature were slowly added
2660 J. Org. Chem., Vol. 73, No. 7, 2008

Preparation of 2,2-Difluorohomopropargyl Carbonyl DeriVatiVes
acetylene 15a (4.0 mmol) and RhCl(PPh3)3 (0.02 mmol). The
reaction mixture was heated at reflux during 12 h. After the reaction
was complete, the solvent was removed under reduced pressure
and the residue was purified by repeated silica gel column
chromatography using EtOAc/hexane (1/10) and then (1/2) as
eluents to afford 16a as a white solid in 92% yield (112 mg) forming
a mixture of regioisomers, 16a-I/16-II ) 1/4. Major isomer 16a-
Acknowledgment. We are grateful to the National Science
Foundation (CHE-0513483), the Ministerio de Educacion y
Ciencia (CTQ2007-61462), and the Generalitat Valenciana (GV/
2007/013) for their financial support and to Professors T. Konno
and T. Ishihara (Kyoto Institute of Technology) for their help
in obtaining HRMS data. B.F. and C.P. express their gratitude
for a predoctoral fellowship and a Ramo´n y Cajal contract,
respectively.
1
II. Mp ) 58-60 °C. H NMR (CDCl3) δ: 4.47 (s, 2H), 4.74 (s,
2H), 4.82 (s, 2H), 7.22 (s, 1H), 7.29-7.36 (m, 5H), 7.42 (d, J )
8.1 Hz, 1H), 7.78 (d, J ) 8.1 Hz, 1H). 19F NMR (CDCl3) δ: -95.7
(s, 2F). 13C NMR (CDCl3) δ: 47.7, 49.4, 63.2, 106.8 (t, J ) 189.9
Hz), 122.3, 124.6, 125.5, 127.1, 127.9, 131.4, 134.1, 143.3, 160.4
(t, J ) 24.5 Hz). HRMS (EI) calcd for C17H15F2NO2 (M+) 303.1070,
found 303.1076.
Supporting Information Available: Analytical and spectro-
scopic data for 3c-h, 5a-d,f-h,j, 7a-e, 8a,b,d, 9a-iso, 9b,c, 10,
14a,b, and 16b-II-16i-II. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO7025965
J. Org. Chem, Vol. 73, No. 7, 2008 2661