AuX3-mediated selective head-to-head dimerization of difluoropropargyl amides

Article abstract of DOI:10.1021/jo9013436

(Chemical Equation Presented) A dimerization of difluoropropargyl amides by reaction with gold(III) halides is described. A reductive elimination of a divinylgold species can be invoked to rationalize its formation. Initial studies of the unusual reactivi

Full text of DOI:10.1021/jo9013436

pubs.acs.org/joc
AuX3-Mediated Selective Head-to-Head Dimerization of
Difluoropropargyl Amides
†
†
†
Santos Fustero,*,†,‡ Paula Bello, Begona Fernandez, Carlos del Pozo, and
~
ꢀ
Gerald B. Hammond§
†
‡
Departamento de Quımica Organica, Universidad de Valencia, E-46100 Burjassot, Spain, Laboratorio de
´
Moleꢀculas Orgaꢀnicas, Centro de Investigacioꢀn Prıncipe Felipe, E-46012 Valencia, Spain, and Department of
ꢀ
§
´
Chemistry, University of Louisville, Louisville, Kentucky 40292
santos.fustero@uv.es; sfustero@cipf.es
Received June 24, 2009
A dimerization of difluoropropargyl amides by reaction with gold(III) halides is described. A
reductive elimination of a divinylgold species can be invoked to rationalize its formation. Initial
studies of the unusual reactivity of these 1,4-dihalo-1,3-dienes have been performed.
Introduction
aldehydes,4 ketones,5 or imines6 catalyzed by gold(I) com-
plexes. More recently, the use of an (NHC)gold(I) fluoride in
a hydrofluorination reaction of alkynes has been reported.7
A gold(I)-catalyzed alkoxyfluorination converted β-hydroxy
ynones to 5-halo-3,30-difluorodihydropyranones, showing
the compatibility of gold catalysis with electrophilic fluor-
inating reagents.8 Finally, the most recent paper in this series
deals with a gold(III)-catalyzed 5-endo-digonal cyclization
followed to dehydrofluorination of gem-difluorohomopro-
pargylamines to render 2-aryl-3-fluoropyrroles.9
In an ongoing project in our laboratory, gem-difluoro
homopropargylic amides have been used as fluorinated
building blocks for the preparation of several nitrogen-
containing fluorinated heterocycles.10 Since alkynes are the
most successful and most frequently used reaction partners
in gold catalysis, we decided to explore the behavior of these
gem-difluoropropargylalkynes in the presence of Au(III)
salts. To our surprise, the unexpected formation of dihalo
dienic systems coming from the head-to-head dimerization
of the starting amides was observed. The optimization of the
reaction conditions, some mechanistic considerations, and
The use of gold compounds in homogeneous organic
reactions, although undervalued for a long time, has experi-
enced an impressive rebirth during the past decade.1 Gold’s
ability to behave as a soft Lewis acid allows it to activate
unsaturated functionalities such as alkynes, alkenes, and
allenes to create carbon-carbon and carbon-heteroatom
bonds under extremely mild conditions.2 Furthermore,
gold complexes efficiently activate sp, sp2, and sp3 carbon-
hydrogen bonds.3 Despite the spectacular development of
gold chemistry, very few reports concerning the use of
fluorinated starting materials have been devised. Most
of them are related to diastereoselective aldol conden-
sations between glycine R-anion equivalents and fluorinated
*To whom correspondence should be addressed. Tel: þ34-963544279.
Fax: þ34-963544938.
(1) (a) Hutchings, G. J.; Brust, M.; Schmidbaur, H. Chem. Soc. Rev. 2008,
37, 1759. (b) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239. (c)
Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180.
~
(2) For selected recent reviews, see: (a) Nunez, E. J.; Echavarren, A.
Chem. Rev. 2008, 108, 3326. (b) Gorin, D. J.; Sherry, B. D.; Toste, F. D.
Chem. Rev. 2008, 108, 3351. (c) Muzart, J. Tetrahedron 2008, 64, 5815. (d)
Shen, H. C. Tetrahedron 2008, 64, 7847.
(3) For selected recent reviews, see: (a) Arcadi, A. Chem. Rev. 2008, 108,
3266. (b) Skouta, R.; Li, C.-J. Tetrahedron 2008, 64, 4917.
(4) (a) Soloshonok, V. A.; Kacharov, A. D.; Hayashi, T. Tetrahedron
1996, 52, 245. (b) Soloshonok, V. A.; Hayashi, T. Tetrahedron Lett. 1994, 35,
1091. (c) Soloshonok, V. A.; Hayashi, T. Tetrahedron Lett. 1994, 35, 2713.
(5) (a) Soloshonok, V. A.; Kacharov, A. D.; Avilov, D. V.; Ishikawa, K.;
Nagashima, M.; Hayashi, T. J. Org. Chem. 1997, 62, 3470. (b) Soloshonok,
V. A.; Kacharov, A. D.; Avilov, D. V.; Hayashi, T. Tetrahedron Lett. 1996,
37, 7845. (c) Soloshonok, V. A.; Hayashi, T.; Ishikawa, K.; Nagashima, N.
Tetrahedron Lett. 1994, 35, 1055.
(6) Hayashi, T.; Kishi, E.; Soloshonok, V. A.; Uozumi, Y. Tetrahedron
Lett. 1996, 37, 4969.
(7) Akana, J. A.; Bhattacharyya, K. X.; Muller, P.; Sadighi, J. P. J. Am.
Chem. Soc. 2007, 129, 7736.
(8) Schuler, M.; Silva, F.; Bobbio, C.; Tessier, A.; Gouverneur, V. Angew.
Chem., Int. Ed. 2008, 47, 7927.
(9) Surmont, R.; Verniest, G.; De Kimpe, N. Org. Lett. 2009, 11, 2920 and
references cited therein.
ꢀ
(10) (a) Fustero, S.; Fernandez, B.; Bello, P.; del Pozo, C.; Arimitsu, S.;
Hammond, G. B. Org. Lett. 2007, 9, 4251. (b) Arimirtsu, S.; Fernandez, B.;
ꢀ
del Pozo, C.; Fustero, S.; Hammond, G. B. J. Org. Chem. 2008, 73, 2656.
7690 J. Org. Chem. 2009, 74, 7690–7696
Published on Web 09/18/2009
DOI: 10.1021/jo9013436
r
2009 American Chemical Society

Fustero et al.
JOCArticle
FIGURE 1. Crystal structure of compound 2a.
preliminary studies of their reactivity are discussed in this
paper.
TABLE 1. Dimerization of gem-Difluoropropargylamides 1
Results and Discussion
When a solution of fluorinated amide 1a (Y = CONHBn)
in CH2Cl2 was treated with AuCl3 the dienic system 2a was
isolated as the major product in 33% yield after 20 h at room
temperature. The structure of compound 2a was unambigu-
ously determined by X-ray analysis (Figure 1).11 The forma-
tion of this derivative implied that two chlorine atoms,
coming from the gold coordination sphere, were involved
in the process. In addition, the structure of the dimer strongly
suggested that an oxidative dimerization of the substrate
occurred by reductive elimination of a gold(III) species.12
Due to the moderate yield of 2a, we decided to optimize the
reaction conditions for its formation since this gold-
mediated transformation has no precedents in the literature.
Thus, different solvents, temperatures, gold sources,
amounts of gold species, and additives were examined in
depth. Among the variety of solvents (CH2Cl2, THF,
CH3OH, PhMe, ClCH2CH2Cl, CH3CN) and temperatures
tested, the best results were initially obtained in refluxing
CH2Cl2 (40% yield). The use of microwave irradiation
allowed us to perform the reaction in 1 h at 70 °C, obtaining
2a in 43% yield (Table 1, entry 1). The use of cationic sources
of gold(III), such as NaAuCl4, did not produce a significant
change in the final yield, while the use of gold(III) bromide
led us to obtain the corresponding diene analogue 2b with
two bromine atoms in 46% yield (Table 1, entry 2).13
Together with diene 2b, three more products were detected
(as can be seen in detail in Scheme 2) in 24% yield, which
indicates that the overall yield of the process is 70%.
entry
1
R1
X
yield of 2a,b (%)
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1c
1d
1d
Bn
Bn
Cl
Br
Cl
Br
Cl
Br
Cl
Br
2a (43)
2b (46)
2c (50)
2d (47)
2e (48)
2f (40)
2g (41)
2h (40)
(S)-Ph(CH)Me
(S)-Ph(CH)Me
allyl
allyl
n-propyl
n-propyl
aIsolated yield after flash column chromatography. bDifferent
amounts of other products 3-5 (20-25% yield) were also obtained
(see Scheme 2).
of dienes 2 was prepared in moderate yields, as depicted in
Table 1.14
A plausible explanation for the reaction mechanism
should start with the metal coordination toward the triple
bond to form complex A, which would undergo a halogen-
ligand exchange to render cationic intermediate B. Since it
can be assumed that the gem-difluoro propargylic unit is like
an R,β-unsaturated functionality,15 it is reasonable to think
that a halogen addition to the terminal alkyne might take
place, affording the vinylgold intermediate C. An analogous
sequence (alkyne-metal coordination, halogen-ligand
exchange, and nucleophilic attack) would generate divinyl
intermediate D, which would finally render dihalo dienes 2
by means of reductive elimination (Scheme 1).
With the optimized reaction conditions in hand
(microwave heating in CH2Cl2 for 1 h in the presence of
30 mol % of the gold source), we extended this methodology
to different gem-difluoropropargylamides 1. Thus, a family
The formation of these highly functionalized head-to-
head dimers 2 is rather unusual, since gold species are not
prone to undergo reductive elimination.16 In addition, the
incorporation of the halogen atoms to the final dienic
(11) For the X-ray structure of 2a, see the Supporting Information.
(12) The formation of a dimer in the reaction of allenyl carbinols with
AuCl3 has been recently reported, although as a side reaction product. A
reductive elimination of gold(III) species was invoked to explain its forma-
tion: Hashmi, A. S. K.; Blanco, M. C.; Fischer, D.; Bats, J. W. Eur. J. Org.
Chem. 2006, 1387.
(14) When internal alkynes in the starting amides 1 were used, the
recovery of the starting material was observed in all cases studied.
(15) We had previously observed this behavior in the intramolecular
hydroamination reaction of fluorinated amide 1a mediated by TBAF. See
ref 10a.
(13) With other catalysts such as PtBr2 or PdCl2 no formation of dimeric
derivatives was detected.
(16) Gold is not usually involved in redox catalytic cycles: Gorin, D. G.;
Toste, D. N. Nature 2007, 446, 395.
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SCHEME 1. Mechanistic Proposal
elimination) to gold(III), and the addition of an external
halogen source. In spite of a recent report on the reoxidation
19
og gold using PhI(OAc)2 and tert-butyl hydroperoxide,20
in our case it was not possible to perform a catalytic
dimerization reaction with the use of these additives in the
presence of a halogen source (KBr or LiCl).21 The use of
22
other additives, such as CuCl2 or 1,4-benzoquinone,23
commonly applied in palladium chemistry, was also unsuc-
cessful.24
A more detailed study of the reaction between 1a and
AuBr3 under the optimized conditions led us to identify other
compounds formed during the process. Together with dimer
2b, formed in 46% yield, we also detected minor amounts of
compounds 3 (4%), 4 (16%), and 5 (4%) (Scheme 2).
The formation of compounds 3 and 4 could be explained
through an alternative reaction pathway. After the activa-
tion of the triple bond by gold coordination (intermediate
A, Scheme 3), an intramolecular hydroamination of the
amidic nitrogen could take place (instead of a halogen inter-
molecular attack) to render intermediate lactam E. Proto-
demetalation followed by double-bond hydration during the
workup process would explain the formation of product 3
(Scheme 3). The second major product 4 could also be
rationalized from intermediate E. This vinylgold intermedi-
ate could coordinate another alkyne molecule to the metal
(intermediate G) followed by halogen exchange and nucleo-
philic attack to afford intermediate I. Reductive elimination
of the divinylgold species would generate the new dienic
structure (intermediate J) that after hydration and subse-
quent loss of HF during the workup would render asym-
metric diene 4 in 16% yield (Scheme 3).25
SCHEME 2. Identification of the Minor Products 3-5
structure is quite surprising.17 Despite the presence of the
amidic nitrogen, which is likely to act as an intramolecular
nucleophile once complex A has been formed, the incorpora-
tion of the halogen atoms is the preferred reaction pathway
(the hydroamination compound derived from the intramo-
lecular attack of the amidic nitrogen was also observed,
although as a minor product; see Scheme 3). Most likely,
the gem-difluoro moiety plays an important role in the
overall process, decreasing the nucleophilicity of the nitro-
gen and, at the same time, activating the alkyne for the
intermolecular nucleophilic addition of the halogen.
Considering the mechanistic proposal shown in Scheme 1,
it became apparent that this process was stoichiometric in
gold.18 Since the halogen atoms of the final products come
from the metal salt, it would be necessary to use 50 mol % of
the gold source to enable the formation of 100% of the final
product. However, when increasing the amount of the
catalyst to 50 mol % lower yields of the desired products
as well as more complex reaction mixtures were obtained.
Attempts to perform the process in a catalytic fashion would
involve the reoxidation of gold(I) (formed after the reductive
Bromoalkene 5 could be explained by proto-demetalation
of the vinylgold species C (Scheme 1) before the coordination
with another alkyne molecule.
In order to evaluate the influence of the fluorine atoms in
the formation of dimers 2, the gem-difluoro moiety was
substituted by two methyl groups in compound 6.26 When
6 was subjected to the optimized conditions in the presence of
AuCl3, a complex mixture was observed (Scheme 4).
Although steric requirements of two methyl groups are
higher than those of two fluorine atoms, this result indicates
the important role played by fluorine in the overall process.
From a synthetic point of view, dimers 2 are fluorinated
1,4-dihalo-1,3-dienes. These systems contain a 1,3-butadiene
skeleton and two halogen atoms for further functionalization,
(19) Kar, A.; Mangu, N.; Kaiser, H. M.; Beller, M.; Tse, M. K. Chem.
Commun. 2008, 386.
(20) Wegner, H. A.; Ahles, S.; Neuburger, M. Chem.;Eur. J. 2008, 14,
11310.
(21) LiCl was very recently used as halogen source in chloropalladation
reactions of a triple bond: Yin, G.; Liu, G. Angew. Chem., Int. Ed. 2008, 47,
5442.
(22) CuCl2 was used both as oxidant additive and halogen source in
palladium-catalyzed reactions: (a) Tang, S.; Yu, Q.-F.; Peng, P.; Li, J.-H.;
Zhong, P.; Tang, R.-Y. Org. Lett. 2007, 9, 3413. (b) Ma, S.; Wu, B.; Zhao, S.
Org. Lett. 2003, 5, 4429.
(17) A similar incorporation of a chlorine atom was previously reported
in the reaction of ethyl propiolate with gold(I) complexes when the reaction
was performed in the presence of BF3 OEt2. Its formation was assumed
(23) 1,4-Benzoquinone was used for the reoxidation of Pd(0) to Pd(II): (a)
€
Piera, J.; Persson, A.; Caldentey, X.; Backvall, J.-E. J. Am. Chem. Soc. 2007,
3
considering that when no other nucleophile is present, the corresponding
gold-alkyne π complex reacts with a chloride ion: Reetz, M. T.; Sommer, K.
Eur. J. Org. Chem. 2003, 3485.
€
€
129, 14120. (b) Piera, J.; Narhi, K.; Backvall, J.-E. Angew. Chem., Int. Ed.
2006, 45, 6914.
(18) The use of gold complexes in stoichiometric reactions is rare. For a
recent example, see: (a) Sahoo, A. K.; Nakamura, Y.; Aratani, N.; Kim, K.
S.; Noh, S. B.; Shinokubo, H.; Kim, D.; Osuka, A. Org. Lett. 2006, 8, 4141.
See also: (b) Fuchita, Y.; Utsinomiya, Y.; Yasutake, M. J. Chem. Soc.,
Dalton Trans. 1 2001, 2330. (c) Zamora, F.; Amo-Ochoa, P.; Fischer, B.;
Schimanski, A.; Lippert, B. Angew. Chem., Int. Ed. 1999, 38, 2274.
(24) When AgSbF5 was used as additive, only the product derived from
the hydroamination of the amidic-nitrogen over the triple bond was ob-
served.
(25) Probably the driving force of this process would be the generation of
more conjugation along the backbone of product 4.
(26) For the preparation of compound 6, see the Supporting Information.
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SCHEME 3. Possible Explanation for the Formation of 3 and 4
SCHEME 4. Dimerization Attempt with Nonfluorinated
Alkyne 6
TABLE 2. Desymmetrization of Dienes 2
entry
2
X
R1
R2
7 (% yield)a
which makes them useful building blocks in the prepa-
ration of conjugated systems. The reaction described here
represents a new protocol for the preparation of 1,4-disub-
stituted 1,3-butadienes that cannot easily be prepared
through other methods.27 Therefore, we decided to perform
preliminary studies of the reactivity of systems 2. We found
that they were unreactive in the Diels-Alder reaction, even
in the presence of a Lewis acid. However, when 2a
was treated with sodium methoxide in methanol, a desym-
metrization reaction of the dienic system occurred yielding
compound 7a, in which only one of the halogen atoms had
been replaced by the oxygen nucleophile (Table 2, entry 1).
Probably, once the first halogen atom is replaced by the
methoxy group, the electronic requirements of the new dienic
system are different, and the addition of a second equivalent
is not favored. The results obtained in the extension of this
protocol to other starting dienes 2 and alcohols are summa-
rized in Table 2.
1
2
3
4
5
6
7
2a
2b
2d
2g
2h
2a
2b
Cl
Br
Br
Cl
Br
Cl
Br
Bn
Bn
Me
Me
Me
Me
Me
Et
7a (94)
7b (85)
7c (88)
7d (60)
7e (65)
7f (55)
7g (50)
(S)-Ph(CH)Me
n-propyl
n-propyl
Bn
Bn
Et
aIsolated yield after flash column chromatography.
SCHEME 5. Reaction of Dienes 2 with CuI
The Ullmann coupling between N-centered nucleophiles
and aryl halides has been successfully extended to vinylic
C-N bond formation.28 The intramolecular version of this
reaction is particularly interesting since it allows the creation
of nitrogen heterocycles. This strategy has been successfully
used in natural product synthesis.29 The application of
Ullmann-type conditions to substrates 2 would lead to the
corresponding fluorinated bis-2-pyrrolidones. Vinyl bro-
mides were found to be good partners in the vinylic coupling.
Thus, when substrate 2b was treated with CuI and Cs2CO3 in
refluxing toluene, the formation of bicyclic system 8b took
place in moderate yield (Scheme 5), while chlorine derivative
2a was unreactive under the same reaction conditions.
Dienes 2d and 2h cyclized under the same conditions to
afford the corresponding bicyclic derivatives 8c,d in 40% and
70% yield, respectively.
(27) For a recent review of the preparation of multiply substituted
butadiene containing building blocks, see: Xi, Z.; Zhang, W.-X. Synlett
2008, 2557.
(28) Zhao, Q.; Li, C. Org. Lett. 2008, 10, 4037 and references cited
therein.
(29) For recent examples, see: (a) Jiang, B.; Tian, H.; Huang, Z.-G.; Xu,
M. Org. Lett. 2008, 10, 2737. (b) Toumi, M.; Couty, F.; Evano, G. Angew.
Chem., Int. Ed. 2007, 46, 572.
J. Org. Chem. Vol. 74, No. 20, 2009 7693

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SCHEME 9. Hydrogenation of Dienic Systems 2a,b
JOCArticle
SCHEME 6. Reaction of Dienes 7 with CuI
cyclized to afford compound 9d, which was subjected with-
out further purification to the Lewis acid-mediated cycliza-
tion. The methoxy side of the diene cyclized under this
conditions to afford bicycle 11 in 66% overall yield
(Scheme 8).
SCHEME 7. Reaction of Dienes 7 with ZnBr2
Finally, hydrogenation reactions were tested on dienes
2a,b. To our surprise, when these substrates were treated
with atmospheric pressure of nitrogen under palladium
catalysis, the unexpected formation of fluorinated olefins
12 was observed, indicating once again the unusual reactivity
shown by these substrates (Scheme 9).30
Conclusions
In conclusion, the microwave irradiation of a solution of
fluorinated amides 1 in the presence of AuX3 (X = Cl, Br) led
to the unexpected formation of head-to-head dimers 2 with
the incorporation of two halogen atoms to the final dienic
backbone. The role of the gem-difluoro moiety in the process
seems to be essential for the unusual behavior of these
alkynes not observed to date in a gold-mediated process.
Preliminary studies on the reactivity of compounds 2 allowed
us to perform the desymmetrization of the dienic structure,
giving rise to derivatives 4. The amidic nitrogen of com-
pounds 2 and 4 was coupled whith the vinylic moiety of the
dienic backbone when bromine was the halogen partner.
Compounds 4 cyclized under acidic conditions involving the
vinyl ether moiety. Efforts directed to the understanding of
the reactivity of 2 and 4 will be reported in due course.
SCHEME 8. Preparation of Asymmetric Bicyclic Derivatives
11
Experimental Section
All microwave experiments were carried out at 0.1 M solution
in a typically 0.5-2 mL vial with an Initiator 2.0, by Biotage.
The solutions were prestirred before irradiation was started. The
absorbance of the solvent was set as “normal”, and 3-4 bar at
70 °C was reached. The reaction time was initiated as soon the
system reached the input temperature, although approximately
2 min was needed to reach it.
General Procedure for the Preparation of Dimers 2. AuX3
(30 mol %) was added to a solution of the corresponding amide
3 (0.5 mmol) in anhydrous CH2Cl2 (0.2 M) in a microwave vial.
The vial was sealed and the solution heated with an air-flow at
70 °C during 1 h under microwave irradiation, and the pressure
was liberated with a needle before removal of the vial cap. The
solution was then filtered, concentrated, and purified by means
of flash chromatography on silica gel with n-hexane-diethyl
ether 7/3 as eluent.
Likewise, bromine-containing dienes 7b,d,h cyclized under
the copper-catalyzed conditions to give monocyclic 2-pyrro-
lidones 9b-d, respectively, in moderate to good chemical
yields (Scheme 6). Again, no reaction was observed in the
chlorine analogue 7a.
As previously mentioned, dienes 2 were unreactive in the
Diels-Alder reaction under usual conditions. However,
when those conditions were applied to compounds 7 in the
presence of a Lewis acid, the clean formation of a new
product was observed. Thus, when 7a,b,e were heated in a
sealed tube in the presence of zinc bromide, cyclized products
10a,b,e were obtained in excellent yields (Scheme 7). Pre-
sumably, the chelation of the Lewis acid with the methoxy
group activates the R-position for a nucleophilic attack of the
amidic nitrogen. In addition, the cyclization is favored by the
loss of HF, giving rise to the highly conjugated pyrrolidones
10 in good chemical yields.
(3Z,4Z)-N1,N6-Dibenzyl-3,4-bis(chloromethylene)-2,2,5,5-tetra-
fluorohexanediamide (2a). Following the general procedure
described above, 50 mg of 2a (43%) was obtained as a white
solid starting from 100 mg of 1a. Mp = 108-110 °C. 1H NMR
(CDCl3, 300 MHz): δ 4.52 (d, J = 5.7 Hz, 4H), 6.78 (s, 2H), 6.89
(br s, 2H), 7.28-7.39 (m, 10H). 13C NMR (CDCl3, 75.5 MHz): δ
Combining the reactions mentioned before, it was possible
to create asymmetric bicyclic derivatives 11. Thus, as a
representative example, when substrate 7e was treated
with CuI, the bromine-containing side of the dienic system
(30) The configuration of the double bond in compound 12 was not
determined.
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JOCArticle
43.7, 112.0 (t, 1JCF= 256.0 Hz), 127.9, 128.0, 129.7 (t, 3JCF= 3.5
Hz), 131.4 (t, 2JCF= 29.3 Hz), 136.4, 162.4 (t, 2JCF= 29.9 Hz).
19F NMR (CDCl3, 282 MHz): δ -101.3 (s, 2 ꢀ 2F). HRMS:
calcd for (Mþ) C22H18Cl2F4N2O2 488.0681, found 488.0687.
Preparation of Compounds 3,10a 4, and 5. Following the
general procedure described above for the synthesis of dimers
2, the reaction of difluoropropargyl amide 1b with AuBr3 led to
the formation of compounds 2b, 3, 4, and 5. Thus, starting from
300 mg of 1b, together with 192 mg of diene 2b (46%), 14 mg of 3
(4%), 112 mg of 4 (16%), and 17 mg of 5 (4%) were obtained.
(Z)-N-Benzyl-3-(1-benzyl-4-fluoro-2-hydroxy-5-oxo-2,5-dihy-
dro-1H-pyrrol-3-yl)-4-bromo-2,2-difluoro-3-butynamide (4).
Colorless oil. 1H NMR (CDCl3, 300 MHz): δ 4.33 (d, J =
15.0 Hz, 1H), 4.48 (dd, J1 = 14.5 Hz, J2 = 15.8 Hz, 1H), 4.58
(dd, J1 = 14.5 Hz, J2 = 5.8 Hz, 1H) 4.98 (d, J = 15.0 Hz, 1H),
5.06 (d, J = 3.8 Hz, 1H), 5.49 (ddd, J1HF = 6.8 Hz, J2 = 3.8 Hz,
(5 mL) and dried over Na2SO4. After complete evaporation of
solvent, the reaction mixture was purified by flash column
chromatography in n-hexane/ethyl acetate (5:1).
1,10-Dibenzyl-4,4,40,40-tetrafluoro-1H,10H-3,30-bipyrrole-5,50-
(4H,40H)-dione (8b). Following the general procedure described
above, 17 mg of 8b (47%) was obtained as a yellow solid starting
1
from 50 mg of 2b. Mp: 198-200 °C. H NMR (CDCl3, 400
MHz): δ 4.63 (s, 4H), 6.68 (t, JHF = 1.3 Hz, 2H), 7.21-7.41
(m, 10H). 13C NMR (CDCl3, 100 MHz): 46.4, 106.1 (t, 2JCF
=
20.9 Hz), 111.9 (t, 1JCF = 251.7 Hz), 127.8, 128.6, 129.3, 132.5
(t, 3JCF = 8.2 Hz), 134.1, 164.6 (t, 2JCF = 28.7 Hz). 19F NMR
(CDCl3, 282 MHz): -115.8 (t, JHF = 1.3 Hz, 4F). HRMS: calcd
for C22H16F4N2O2 416.1148, found 416.1146.
(Z)-N-Benzyl-3-(1-benzyl-4,4-difluoro-5-oxo-4,5-dihydro-1H-
pyrrol-3-yl)-2,2-difluoro-4-methoxybut-3-enamide (9b). Follow-
ing the general procedure described above, starting from 20 mg
of 7b, 11 mg of 9b was obtained as a yellow oil (65%). 1H NMR
(CDCl3, 300 MHz): δ 3.61 (s, 3H), 4.49 (d, J = 6 Hz, 2H), 4.60 (s,
2H), 6.64 (s, 1H), 6.66 (br s, 1H), 6.73 (t, JHF = 2.1 Hz, 1H),
7.22-7.40 (m, 10H). 13C NMR (CDCl3, 100 MHz): 43.6, 46.3,
61.8, 103.6 (t, 2JCF = 25.3 Hz), 108.7 (t, 2JCF = 21.8 Hz), 112.7
(t, 1JCF = 251.6 Hz), 114.3 (t, 1JCF = 251.6 Hz), 127.8, 127.9,
127.9, 128.4, 128.8, 129.1, 133.6 (t, 3JCF = 7.8 Hz), 134.5, 137.1,
J
3HF = 2.0 Hz, 1H), 7.06 (br s, 1H), 7.08 (dd, J1HF = 3.4 Hz,
J2HF = 1.9 Hz, 1H), 7.27-7.40 (m, 10H). 13C NMR (CDCl3,
75.5 MHz): 43.4, 44.1, 78.0 (dd, 3JCF = 8.4 Hz, 4JCF = 5.2 Hz),
112.8 (dd, 1JCF = 252.3 Hz, 1JCF = 262.0 Hz), 119.4 (m), 125.2,
127.8, 128.0, 128.4, 128.8, 129.0, 135.5, 136.1, 150.3 8 (d, 1JCF
=
291.3 Hz), 160.6 (d, 2JCF = 31 Hz), 163.1 (t, 2JCF = 29.3 Hz).
19F NMR (CDCl3, 282 MHz): δ -98.9 (dd, JFF = 272.1 Hz,
1
5JFF = 2 Hz, 1F), -101.9 (dddd, 1JFF = 272.1 Hz, 5JFF = 4.6
Hz, JFH = 3.4 Hz, JFH = 2 Hz, 1F), -137.4 (dddd, 5JFF = 4.6
151.6 (t, JCF = 6.4 Hz), 163.6 (t, JCF = 29.6 Hz), 164.6 (t,
2JCF = 29.6 Hz). 19F NMR (CDCl3, 282 MHz): -100.9 (s, 2F),
-113.7 (s, 2F). HRMS: calcd for C23H20F4N2O3 448.1410,
found 448.1415.
3
2
5
Hz, JFF = 2 Hz, JFH = 6.8 Hz, JFH = 1.8 Hz, 1F). HRMS:
calcd for (Mþ) C22H18BrF3N2O3 494.0453, found 494.0462.
(Z)-N-Benzyl-4-bromo-2,2-difluoro-3-butynamide (5). White
solid. Mp: 65-67 °C. 1H NMR (CDCl3, 300 MHz): δ 4.54 (d,
J = 5.7 Hz, 2H), 6.66 (dt, J1HF = 11.6 Hz, J2 = 8.4 Hz, 1H),
6.74 (br s, 1H), 6.78 (dt, J1 = 8.4 Hz, J2 = 1.5 Hz), 7.30-7.40
General Procedure for the Preparation of Compounds 10. A
solution of ZnBr2 (34 mg, 0.15 mmol) and the corresponding
1,3-diene 7 (0.10 mmol) in anhydrous dichloromethane (0.1 M)
was heated in a sealed tube at 90 °C for 2 h. The reaction was
then quenched with distilled water (5 mL) and extracted with
dichloromethane (3 ꢀ 5 mL). The combined organic layers were
washed with brine (5 mL) and dried over Na2SO4. After
complete evaporation of solvent, the reaction mixture was
purified by flash column chromatography in n-hexane/ethyl
acetate (3:1).
(m, 5H). 13C NMR (CDCl3, 75.5 MHz): δ 43.7, 113.1 (t, 1JCF
=
248.6 Hz), 115.5 (t, 3JCF = 9.9 Hz), 127.4 (t, 2JCF = 28.0 Hz),
127.9, 128.0, 128.9, 136.4, 162.6 (t, 2JCF = 30.0 Hz). 19F NMR
(CDCl3, 282 MHz): δ -100.8 (d, JFH = 11.6 Hz, 2F). HRMS:
calcd for (Mþ) C11H10BrF2NO 288.9914, found 288.9919.
General Procedure for the Preparation of Asymmetric Dimers
7. To a solution of the corresponding diene 2 (0.1 mmol) in
anhydrous THF (0.1 M) at 0 °C was added dropwise a solution
of sodium alkoxide (0.25 mmol, 0.5 M solution of MeONa/
MeOH or 21 wt % EtONa/EtOH), and the mixture was allowed
to reach room temperature. The solution was stirred for an
additional 6-10 h at rt, hydrolyzed with water (5 mL), and
extracted with CH2Cl2 (3 ꢀ 5 mL). The combined organic layers
were washed with brine (5 mL), dried over anhydrous Na2SO4,
and purified after solvent evaporation by means of flash chro-
matography with hexanes/ethyl acetate 3:1 as eluent.
(Z)-N-Benzyl-3-(1-benzyl-4-fluoro-2-methoxy-5-oxo-2,5-dihydro-
1H-pyrrol-3-yl)-4-chloro-2,2-difluorobut-3-enamide (10a). Follow-
ing the general procedure described above, starting from 50 mg of
7a, 34 mg of 10a were obtained as a colorless oil (70%). 1H NMR
(CDCl3, 300 MHz): δ 3.04 (s, 3H), 4.13 (d, J = 14.5 Hz, 1H), 4.52
(d, J = 5.6 Hz, 2H), 4.96 (d, J = 14.5 Hz, 1H), 5.4 (d, J = 6.2 Hz,
1H), 6. 74 (br s, 1H), 6.92 (s, 1H). 13C NMR (CDCl3, 75.5 MHz):
43.8, 43.7, 49.8, 83.3 (dt, 3JCF = 5.9 Hz, 4JCF = 2 Hz), 112.9 (t,
1JCF = 257.7 Hz), 119.0 (td, 3JCF = 1.8 Hz, 4JCF = 0.6 Hz), 125.9
2
3
(td, JCF = 26.4 Hz, JCF = 4.9 Hz), 127.9, 128.0, 128.1, 128.6,
128.8, 128.9, 130.4 (dt, 2JCF = 6.4 Hz, 3JCF = 5.2 Hz), 135.6, 136.3,
149.5 (d, 1JCF = 293.7 Hz), 161.0 (d, 2JCF = 31.6 Hz), 161.7 (t,
(3Z,4Z)-N1,N6-Dibenzyl-3-(chloromethylene)-2,2,5,5-tetra-
fluoro-4-(methoxymethylene)hexanediamide (7a). Following
the general procedure described above, 28 mg of 7a (94%)
was obtained as a colorless oil starting from 30 mg of 2a. 1H
NMR (CDCl3, 300 MHz): δ 3.61 (s, 3H), 4.49 (d, J = 5.8 Hz,
2H), 4.50 (d, J = 5.7 Hz, 2H), 6.45 (s, 1H), 6.66 (s, 1H), 6.86 (br
s, 1H), 6.98 (br s, 1H), 7.29-7.38 (m, 10H). 13C NMR (CDCl3,
75.5 MHz): 43.5, 43.7, 61.7, 106.8 (t, 2JCF = 27.6 Hz), 112.6 (t,
2JCF = 29 Hz). 19F NMR (CDCl3, 282 MHz): -99.1 (dd, JFF
279.3 Hz, JFF = 17.2 Hz, 1F), -100.8 (dd, JFF = 279.3 Hz, JFF
=
=
17.2 Hz, 1F), -128.1 (ddd, J1FF = J2FF = 17.2 Hz, JFH = 6.2 Hz).
HRMS: calcd for C23H20ClF3N2O3 464.1114, found 464.1108.
4-(4,4-Difluoro-5-oxo-1-propyl)-4,5-dihydro-1H-pyrrol-3-yl)-
3-fluoro-5-methoxy-1-propyl-1H-pyrrol-2(5H)-one (11). Follow-
1
1JCF = 255.8 Hz), 113.0 (t, JCF = 252.9 Hz), 127.7, 127.8,
ing a two-step procedure, the CuI-mediated cyclization
3
127.9, 128.0, 128.5 (t, JCF2 = 5.2 Hz), 136.6, 137.2, 155.4 (t,
(preparation of compounds 8) followed by ZnBr2-mediated
cyclization (preparation of compounds 10), starting from 15
mg of 7h, produced 8 mg of 11 as a yellow oil (66%). 1H NMR
(CDCl3, 300 MHz): δ 0.94 (t, J = 7.3 Hz, 3H), 0.96 (t, J = 7.3 Hz,
3H), 1.67 (m, 4H), 3.03 (s, 3H), 3.11 (ddd, J1 =14Hz;J2 =8.4 Hz;
J3 = 6 Hz, 1H), 3.47 (ddd, J1 = 21 Hz; J2 = 14 Hz; J3 = 7.1 Hz,
1H), 3.49 (ddd, J1 = 21 Hz; J2 = 14 Hz; J3 = 7.2 Hz, 1H), 3.57
(ddd, J1 = 15.8 Hz; J2 = 8.4 Hz; J3 = 7.1 Hz, 1H), 5.51 (d, J = 5.8
Hz, 1H), 7.23 (d, J =1.6 Hz, 1H). 13CNMR (CDCl3, 100MHz):δ
2
3JCF = 6.3 Hz), 162.9 (t, JCF = 29.8 Hz), 163.9 (t, JCF
=
31.0 Hz). 19F NMR (CDCl3, 282 MHz): δ -110.0 (s, 2F),
-111.1 (s, 2F). HRMS: calcd for (Mþ) C23H21ClF4N2O3
485.1255, found 485.1254.
General Procedure for the Preparation of Compounds 8 and 9.
A solution of CuI (4 mg, 0.02 mmol, 20 mol %), Cs2CO3 (98 mg,
0.3 mmol), and the corresponding 1,3-diene 2 (0.10 mmol) in
anhydrous toluene (0.09 M) was heated in a sealed tube at 80 °C
during 15 h. The reaction mixture was then quenched with
distilled water (5 mL) and extracted with ethyl acetate (3 ꢀ
5 mL). The combined organic layers were washed with brine
3
10.9, 11.3, 21.4, 21.8, 41.6, 44.7, 48.5, 82.6 (d, JCF = 6.9 Hz),
105.7 (td, 2JCF = 22.4 Hz; 3JCF = 6.8 Hz), 110.7 (t, 1JCF = 252.2
Hz), 114.2, 139.7 (td, JCF = 8.5 Hz; JCF = 8.5 Hz), 147.0
3
4
J. Org. Chem. Vol. 74, No. 20, 2009 7695

Fustero et al.
JOCArticle
(d, 1JCF = 290.2 Hz), 161.8 (d, 2JCF = 29.7 Hz), 165.3 (t, 2JCF
29.7 Hz). 19F NMR (CDCl3, 282 MHz): δ -115.4 (ddd, JFF
=
=
7.22-7.37 (m, 10H). 13C NMR (CDCl3, 75.5 MHz): δ 16.4
3
1
(t, JCF = 4.4 Hz), 44.6, 117.3 (t, JCF = 253.6 Hz), 135.3 (t,
2JCF = 23 Hz), 129.0, 129.4, 130.3, 140.1, 164.9 (t, 2JCF = 31.3
Hz). 19F NMR (CDCl3, 282 MHz): δ -122.247 (s, 4F). HRMS:
calcd for C22H22F4N2O2 422.1617, found 422.1605.
13 Hz; J1FH = J2FH = 2.1 Hz, 2F), -133.4 (tdd, JFF = 13 Hz;
J1
C15H19F3N2O3 332.1348, found 332.1345.
= 5.6 Hz; J2
= 1.3 Hz, 2F). HRMS: calcd for
FH
FH
(Z)-N1,N6-Dibenzyl-2,2,5,5-tetrafluoro-3,4-dimethylhex-3-
dienamide (12). A solution of diene 2a (20 mg, 0.1 mmol) in
anhydrous methanol (5 mL) was introduced in a pressure
reactor, and 0.4 mg of 10% Pd-C was added. The suspension
was stirred at room temperature for 20 h under 15 atm of
hydrogen. After this time, the pressure was released and the
mixture filtered through a pad of Celite and washed with EtOAc
(3 ꢀ 5 mL). Evaporation of the solvents rendered 15 mg of
compound 12 (85%) as a white solid (without further
purification). Starting from 20 mg of 2b, 12.5 mg of 12 was
obtained (85%). Mp: 168-170 °C. 1H NMR (CDCl3, 300
MHz): δ 1.92 (t, J = 2.2 Hz, 6H), 4.49 (d, J = 6.2 Hz, 4H),
Acknowledgment. Financial support of this work by the
ꢀ
Ministerio de Educacion y Ciencia (Grant No. CTQ2007-
61462) is gratefully acknowledged. P.B. and B.F. express
their thanks for predoctoral fellowships. C.d.P. thanks the
ꢀ
same institution for a Ramon y Cajal contract.
Supporting Information Available: Experimental proce-
dures and NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
7696 J. Org. Chem. Vol. 74, No. 20, 2009