Intramolecular hydroamination of difluoropropargyl amides: Regioselective synthesis of fluorinated β- and γ-lactams

Article abstract of DOI:10.1021/ol701811z

Functionalized gem-difluoro β- and γ-lactams were synthesized through a novel intramolecular hydroamination reaction of difluoropropargyl amides. β-Lactams were obtained via a Baldwin disfavored 4-exo-digonal cyclization using palladium acetate as the cat

Full text of DOI:10.1021/ol701811z

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4251-4253
Intramolecular Hydroamination of
Difluoropropargyl Amides:
Regioselective Synthesis of Fluorinated
|
â
- and γ-Lactams
Santos Fustero,*,†,‡ Begon˜a Ferna´ndez,† Paula Bello,† Carlos del Pozo,†
Satoru Arimitsu,§ and Gerald B. Hammond*,§
Departamento de Qu´ımica Orga´nica, UniVersidad de Valencia, E-46100 Burjassot,
Spain, Laboratorio de Mole´culas Orga´nicas, Centro de InVestigacio´n Pr´ıncipe Felipe,
E-46013 Valencia, Spain, and Department of Chemistry, UniVersity of LouisVille,
LouisVille, Kentucky 40292
santos.fustero@uV.es; gb.hammond@louisVille.edu
Received July 27, 2007
ABSTRACT
Functionalized gem-difluoro
amides. -Lactams were obtained via a Baldwin disfavored 4-exo-digonal cyclization using palladium acetate as the catalyst, whereas
were produced under basic conditions. Acid hydration of -lactams produced ketoamides or hemiaminals selectively.
â
- and
γ
-lactams were synthesized through a novel intramolecular hydroamination reaction of difluoropropargyl
â
γ-lactams
γ
Catalytic hydroamination of multiple carbon-carbon bonds
constitutes one of the most efficient methodologies to create
carbon-nitrogen bonds.1 The intramolecular version of this
process is an attractive method to generate nitrogen hetero-
cycles, converting starting materials into desired products
in a single operation, without the formation of side products
and with high atom efficiency. To overcome the high
activation energy required for the direct addition of amines
or their derivatives across multiple carbon-carbon bonds, a
variety of catalytic and noncatalytic methods have appeared
in the literature.2 The synthesis of gem-difluoromethylene-
containing compounds has witnessed a growing interest
because of their interesting biological activities.3 Very
recently, we described the regioselective synthesis of six-
to eight-membered ring fluorinated lactams through a tandem
ring-closing metathesis-isomerization protocol.4 However,
this methodology is not amenable for the synthesis of four-
and five-membered ring difluoro lactams. We decided to
† Universidad de Valencia.
‡ Centro de Investigacio´n Pr´ıncipe Felipe.
§ University of Louisville.
| Dedicated to Prof. Kenji Uneyama on the occasion of his 65th birthday.
(1) For reviews of hydroamination, see: (a) Hong, S.; Marks, T. J. Acc.
Chem. Res. 2004, 37, 673. (b) Nakamura, I.; Yamamoto, Y. Chem. ReV.
2004, 104, 2127. (c) Alonso, F.; Beletskaya, I.; Yus, M. Chem. ReV. 2004,
104, 3079. (d) Bytschkov, I.; Doye, S. Eur. J. Org. Chem. 2003, 935. (e)
Pohlki, F.; Doye, S. Chem. Soc. ReV. 2003, 32, 104. (f) Beller, M.; Breindl,
C.; Eichberger, M.; Hartung, C. G.; Seayad, J.; Thiel, O. R.; Tillack, A.;
Trauthwein, H. Synlett 2002, 1579. (g) Seayad, J.; Tillack, A.; Hartung, C.
G.; Beller, M. AdV. Synth. Catal. 2002, 344, 795. (h) Cacchi, S. J.
Organomet. Chem. 1999, 576, 42. (i) Mu¨ller, T.; Beller, M. Chem. ReV.
1998, 98, 675.
(2) Chianese, A. R.; Lee, S. J.; Gagne´, M. R. Angew. Chem., Int. Ed.
2007, 46, 4042 and refs cited therein.
(3) Mae, M.; Hong, J. A.; Hammond, G. B.; Uneyama, K. Tetrahedron
Lett. 2005, 46, 1787 and refs cited therein.
(4) 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.
10.1021/ol701811z CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/19/2007

study the construction of these small heterocycles using
difluoropropargyl bromides 4 as fluorinated building blocks.
This synthon has been used for the preparation of several
valuable intermediates, such as fluorinated allenes, fluoro-
dienes, and other functionalized fluoroalkynes.5 We are now
pleased to report that base treatment of amide 1sobtained
from 4sled to the formation of γ-lactams 2 via a nucleo-
philically driven 5-endo-digonal cyclization mode (Scheme
1, Via b), while the use of a palladium catalyst afforded the
diastereomeric mixture of (Z)-3a and (E)-3a was obtained
in 63% yield (13:1) (Table 2, entry 1).6,7 The extension of
Table 2. Synthesis of â-Lactams 3 and 4
entry
substratea
(Z)-3 + (E)-3 (yield %)
Z/Eb
Scheme 1. Synthetic Strategy
1
2
3
4
5
6
1b
1c
1d
1e
1f
(Z)-3a + (E)-3a (63)
(Z)-3b + (E)-3b (54)
(Z)-3c + (E)-3c (33)
(Z)-3d + (E)-3d (40)
(Z)-3e + (E)-3e (34)
(Z)-3f + (E)-3f (34)
13:1
>50:1
14:1
10:1
10:1
1g
10:1
a
Substrate 1a was inert under the reaction conditions, probably due to
b
steric hyndrance of the TIPS group. Diastereoisomeric ratios were
determined by 19F NMR.
this protocol to other amides, 1, led to the formation of the
corresponding â-lactams (Z)-3 and (E)-3 in moderate yields
and good selectivities (Table 2). â-Lactams 3 were relatively
unstable in solution; for example, when a CH2Cl2 solution
of 3a was stirred at rt for one week, it evolved into ketone
7a (see Table 4, entry 1).
unexpected â-lactams 3, via a 4-exo-digonal cyclization
mode (Scheme 1, Via a).
Amides 1 were efficiently prepared using a Grignard
derivative of 4 that was treated with methyl chloroformate
followed by reaction with an amine in the presence of either
sodium hydride in THF at -50 °C (method A) or trimethyl
aluminum in DCM at 0 °C (method B) (Table 1).
Scheme 2. Possible Pd-Catalyzed 4-exo-dig Cyclization
Table 1. Preparation of Fluorinated Propargyl Amides 1
entry
R1
R2
methodd
1 (yield %)
1
2
3
4
5
6
7
TIPSa
Ph
Ph
Ph
Ph
Bn
Bn
PMPb
Allyl
(S)-PhCH(Me)
Bn
Bn
A
A
B
A
B
A
A
1a (80)
1b (75)
1c (70)
1d (85)
1e (85)
1f (70)
1g (54)
A possible mechanism (Scheme 2) may involve initial
alkyne activation through coordination of the triple bond with
palladium(0). Literature reports suggest8 that the p character
3-thienyl
MMPc
(5) (a) Hammond, G. B. J. Fluorine Chem. 2006, 127, 476. (b) Xu, B.;
Mae, M.; Hong, J. A.; Li, Y.; Hammond, G. B. Synthesis 2006, 803 and
refs cited therein.
(6) Other sources of paladium were also tested, such us Pd(PPh3)4, PdCl2-
(PPh3)2, and Pd2(dba)3‚CHCl3. The reaction was also performed with other
bases (K2CO3), solvents (DMF, DCM), temperatures, and reaction times.
In all cases tested, less satisfactory results were obtained.
(7) The stereochemistry of the â-lactams was determined by NOESY
experiments over the diastereomeric mixture of compounds (Z)-3b + (E)-
3b that were unseparable by flash chromatography.
a
b
c
TIPS ) Triisopropylsilyl. PMP ) p-MeOC6H4. MMP ) 2-Me-4-
MeO-C6H3. d Method A: NaH/R2NH2/THF/-50 °C/1-3 h. Method B:
AlMe3/R2NH2/CH2Cl2/0 °C/2-4 h.
Our initial intramolecular hydroamination studies were
carried out with alkyne 1b using several palladium catalysts.
With palladium acetate in the presence of Et3N in THF, a
(8) (a) Jacobson, S.; Carty, A. J.; Mathew, M.; Palemik, G. J. J. Am.
Chem. Soc. 1974, 96, 4330. (b) McGinnety, J. A. J. Chem. Soc. Dalton
Trans. 1974, 1038.
4252
Org. Lett., Vol. 9, No. 21, 2007

of the alkyne carbons increases through this interaction, thus
resembling an sp2-like hybridization.
Table 4. Reaction of Compounds 2 with R3OH/H+
This pseudohybridization could favor both 4-exo-dig and
5-endo-dig modes of cyclization, but the presence of the gem-
difluoro moiety should predispose the R-position for in-
tramolecular nucleophilic attack by the amidic nitrogen, thus
favoring a 4-exo-dig cyclization mode.
Considering the increased importance of gold catalysis
in hydroamination reactions,9 we also explored the behavior
of amides 1 in the presence of gold salts [i.e., AuCl, AuCl/
AgOTf or AgSbF6, AuCl3, Au(PPh3)OTf]. All cyclization
attempts were unsuccessful, and either complex mixtures
or, when identified, no hydroamination products were
obtained.10
We decided then to seek the base-mediated activation of
the amidic nitrogen to produce γ-lactams 2. Of all bases tried
(DBU, NaH, i-Pr2NEt, LiN(TMS)2, KOH, t-BuOK, TBAF),
the best results were obtained using 1.1 equiv of TBAF at rt
(Table 3). In this case, the triple bond is electron deficient,
entry
substrate
R3
acid
6, 7 (% yield)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2g
2g
2g
H
H
H
H
H
H
H
HCl 3 M
HCl 3 M
HCl 3 M
HCl 3 M
HCl 3 M
HCl 3 M
HCl 3 M
H2SO4
7a (94)
7b (66)
7c (62)
7d (66)
7e (60)
7f (62)
6g (98)
6h (94)
6i (80)
6j (63)
Mea
CF3CH2
CH3COc
b
HBF4
10
-
a
MeOH was used as solvent with a catalytic amount of 98% sulfuric
b
acid. Trifluoroethanol was used as solvent with a catalytic amount of
tetrafluoroboric acid. c The reaction was performed in refluxing acetic acid.
Table 3. Hydroamination Mediated by TBAF
ketones 7 in good yields (Table 4, entries 2-6). With 2g
(R1 ) H) the product was isolated as the corresponding
hemiaminal 6g (Table 4, entry 7). Using the same strategy,
it was also possible to introduce alkoxy groups instead of
the hydroxyl functionality. With sulfuric acid as the catalyst,
compound 2g reacts with methanol in very good yield (Table
4, entry 8). The best results with trifluoroethanol were
obtained when HBF4 was the acid of choice (Table 4, entry
9). Finally, when the reaction was performed in refluxing
acetic acid, the corresponding acetate was isolated in good
yield (Table 4, entry 10).
entry
substrate
time (h)
2 (yield %)
1
2
3
4
5
6
7
1b
1c
1d
1e
1f
1.5
2
3
0.5
1
3
2a (61)
2b (60)
2c (64)
2d (62)
2e (66)
2f (67)
2g (78)
1g
1ha
In conclusion, we have described the regioselective
preparation of fluorinated â- and γ-lactams through an
intramolecular hydroamination reaction of difluoropropargyl
amides. Under palladium catalysis, the reaction takes place
in a 4-exo-digonal cyclization mode, in sharp contrast with
other palladium-catalyzed hydroaminations, that showed a
strong preference for the formation of a five-membered ring.
The activation of the amidic nitrogen with TBAF led to the
formation of γ-lactams.
3
a
Substrate 1h was obtained in 98% yield from 1a by treatment with
TBAF/AcOH (see Supporting Information).
so a base-promoted nucleophilic addition occurs. Since a
5-endo-digonal cyclization is favored, the formation of
γ-lactam 2 is expected.
When 2a was heated for 1 h in the presence of a catalytic
amount of HCl (3 N), ketone 7a was obtained in almost
quantitative yield (Table 4, entry 1). The same conditions
applied to substrates 2b-f afforded the corresponding
Acknowledgment. We thank the Ministerio de Educacio´n
y Ciencia (CTQ2007-61462), the Generalitat Valenciana
(GR03-193 and ACOMP07/031), and the National Science
Foundation (grant CHE-0513483 to G.B.H.) for generous
financial support. B.F. and P.B. express their thanks for
predoctoral fellowships, and C.P. expresses his gratitude for
a Ramo´n y Cajal contract. The authors thank Dr. Ana Cun˜at
(University of Valencia) for the NMR experiments.
(9) (a) Widenhoefer, R. A.; Han, X. Eur. J. Org. Chem. 2006, 4555. (b)
Patil, N. T.; Yamamoto, Y. ArkiVoc 2007, X, 121.
(10) For example, when substrates 1b (R1 ) Ph) and 1h (R1 ) H) were
treated with AuCl3 (10 mol %)/AcOH (3 equiv), the corresponding
hemiaminal 6g or ketone 7a was obtained as the only identifiable product.
That can be explained assuming activation of the triple bond by the metal,
and final gold displacement from the water, indicating that the amidic
nitrogen is not nucleophilic enough to perform the cyclization.
Supporting Information Available: Experimental pro-
cedures and NMR spectra for 1-7. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL701811Z
Org. Lett., Vol. 9, No. 21, 2007
4253