[1,5]-hydride transfer/cyclizations on alkynyl fischer carbene complexes: Synthesis of 1,2-dihydroquinolinyl carbene complexes and cascade reactions

Article abstract of DOI:10.1002/anie.200802268

(Chemical Equation Presented) Trigger happy: A new cascade process initiated by an unprecedented [1,5]-hydride transfer/cyclization of ortho-aminophenyl alkynyl Fischer carbene complexes leads to the formation of new 1,2-dihydroquinolinyl carbene complexes and 5,6-dihydrophenantridine derivatives (see scheme).

Full text of DOI:10.1002/anie.200802268

Communications
DOI: 10.1002/anie.200802268
Synthetic Methods
[1,5]-Hydride Transfer/Cyclizations on Alkynyl Fischer Carbene
Complexes: Synthesis of 1,2-Dihydroquinolinyl Carbene Complexes
and Cascade Reactions**
JosØ Barluenga,* Martín Faæanµs-Mastral, Fernando Aznar, and Carlos ValdØs
Cascade [1,5]-hydride transfer/cyclization reactions are syn-
thetically powerful strategies for the construction of hetero-
triple bonds, despite the synthetic power of this type of
cascade isomerization. In contrast, ortho-alkynyl anilines
undergo metal-catalyzed 5-endo-dig cycloisomerizations
leading to indole derivatives.[4]
À
À
cycles involving a C H to C C transformation. The most
typical examples of this relatively unusual reaction sequence
involve the cyclization of N-N-dialkyl-2-vinylanilines,[1] which
results from the tert-amino effect[2] (Figure 1a). In these
As a part of our work on the chemistry of alkynyl Fischer
carbene complexes,[5] we turned our attention to the study of
chromium
ortho-aminophenylalkynyl
complexes
(1;
Scheme 1). Alkynyl carbene complex 1a was synthesized by
standard procedures,[6] and it was stable at room temperature,
however, when a solution of 1a in THF was heated at 908C in
a sealed tube, new carbene complex 2a was isolated in 98%
yield after the workup (Scheme 1).
Figure 1. Examples of [1,5]-hydride transfer/cyclization cascades.
processes the first and rate-limiting step comprises of a
hydride migration from the carbon atom, a to the hetero
atom, to the electrophilic position of the vinyl group. Thus,
suitable systems for the tandem reaction must feature a
heteroatom, to stabilize the carbocation that develops upon
hydride migration, and a strong electron-withdrawing group
on the terminal position of the double bond. More recently,
this strategy has been extended to functionalize the a position
Scheme 1. Synthesis of 1,2-dihydroquinolinyl carbene complex 2a.
The formation of carbene complex 2a can be explained by
an intramolecular two-step process which involves the
migration of one hydride, from the benzylic carbon center
to the highly electrophilic b carbon of the triple bond of
À
of ethers and carbamates, and even tertiary benzylic C H
bonds in processes promoted by Lewis acid catalysts (Fig-
ure 1b).[3]
To the best of our knowledge, there is no precedent for alkynyl carbene complex 1a, to generate zwitterionic inter-
analogous hydride-transfer-promoted cyclizations involving
mediate I. The subsequent cyclization step would then lead to
new carbene complex 2a. The presence of the strong electron-
withdrawing effect of the chromium pentacarbonyl moiety is
essential to provide a proper scenario for the [1,5]-hydride
transfer/cyclization in which the internal sp carbon atom
participates. This chemical behavior does not have any
precedent in the chemistry of Fischer carbene complexes.
Moreover, to the best of our knowledge, this reaction
represents the first example of a hydride migration/cyclization
cascade involving a triple bond.
[*] Prof. J. Barluenga, Dr. M. Faæanµs-Mastral, Prof. F. Aznar,
Dr. C. ValdØs
Instituto Universitario de Química Organometµlica “Enrique
Moles” Unidad Asociada al C.S.I.C.
Universidad de Oviedo, Juliµn Clavería, 8, 33006 Oviedo (Spain)
Fax: (+34)98-510-3450
E-mail: barluenga@uniovi.es
[**] Financial support from the DGICYT (CTQ2007-61048/BQU). A FPU
predoctoral fellowship to M.F.-M. is gratefully acknowledged. We
also thank Dr. Angel L. Suµrez for help in the X-ray structure
determination.
An NMR study revealed that a temperature of 708C is
necessary for the reaction to take place, although 908C is a
more convenient temperature as it provides the product after
a shorter reaction time.
Supporting information for this article is available on the WWW
underhttp://dx.doi.org/10.1002/anie.200802268.
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Next, we tried to determine the scope of this reaction by
using different ortho-aminophenylalkynyl carbene complexes
(1), in which the nitrogen atom and the phenyl ring
substituents were modified.
As shown in Table 1, N-benzylalkynyl carbene complexes
undergo this hydride transfer/cycloaddition process with
moderate to very good yields. The substituents on the tertiary
amine have a significant influence on the reaction time and
Scheme 2. Competition reaction of alkynyl carbene complex 1h.
Table 1: Synthesis of 1,2-dihydroquinolinyl carbene complexes (2) by a
[1,5]-hydride transfer/cyclization process.
I as the rate-limiting step in the mechanism depicted in
Scheme 1. Thus, the reaction will be favored in the presence
of substituents that can stabilize the positive charge that
develops upon hydride migration.
This mechanistic proposal is also consistent with DFT
computations carried out on model system A.[7,8] We found
that the transformation of A1 into A4 takes place through the
stepwise mechanism depicted in Scheme 3.
Entry
1
R1
R2
R3
2
t [h]
Yield [%]
As expected by the experimental observations, the key
step of the sequence is the hydrogen atom migration that
leads to zwitterionic species A2. We obtained an activation
free energy of 29.6 kcalmolÀ1 for this step,[9] which is a
reasonable barrier for a process that takes place at 908C. The
hydrogen atom migration occurs in an asynchronous con-
certed manner through a late transition state, as shown by the
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1 f
Ph
Ph
Ph
4-Br-Ph
4-Tol
Ph
Ph
Ph
Ph
4-Br-Ph
4-Tol
H
H
2a
2b
2c
2d
2e
2 f
2g
2.5
2
6
10
2
9
98
95
72
63
96
65
85
Me
Cl
H
H
H
1g
Ph
tBu
H
1.5
À
À
shorter distance found for the newly formed C H bond (C5
À
H = 1.25 Š) compared to the C H bond that is being broken
À
the yield of the reaction. High yields are obtained when the
initial alkynyl carbene complex has either benzyl or alkyl-
(C1 H = 1.44 Š). The structure obtained for TS(A1–A2)
(TS = transition state)resembles the transition state of a [1,5]-
benzyl substituents on the nitrogen atom (Table 1, entries 1, 2, sigmatropic rearrangement. Indeed, taking into account the
and 5). A decrease in the product yield is observed when the
initial carbene complex bears an electron-withdrawing group,
such as a chloro or bromo substituent, on the benzene rings
(Table 1, entries 3 and 4). The decrease in the yields is
associated with longer reactions times because part of the
product may decompose as a result of the extended exposure
to high temperatures.
When the reaction was carried out with nonsymmetric
carbene complex 1 f the corresponding quinolinyl carbene
complex 2 f was obtained in a 65% yield after 9 hours
(Table 1, entry 6). Notably, the reaction proceeds with total
chemoselectivity, as only migration of the benzylic hydrogen
atom was observed. The use of a bulkier group, such as a neo-
pentyl group, gave rise to carbene 2g in better yield after a
shorter reaction time (Table 1, entry 7). Again, only migration
of the benzylic hydrogen atom was observed.
In the case of alkynyl Fischer carbene complex 1h, which
bears both a benzyl and a 4-methoxybenzyl group as
substituents on the nitrogen atom (Scheme 2), the formation
of two reaction products, 2h and 2i, in a 3:1 ratio was
observed. The major product, 2h, derives from the intra-
molecular addition of a hydride from the 4-methoxybenzyl
group, showing that the presence of an electron-donor group
in the phenyl ring favors the formation of the 1,2-dihydro-
quinolinyl carbene complex.
Scheme 3. Calculated energies for the formation of dihydropyridine A4.
The values are the relative Gibbs free energies (kcalmolÀ1) obtained at
the B3LYP/6-311++G**+LANL2DZ//B3LYP/6-31G*+LANL2DZ
level.
The results presented above with respect to the influence
of the substituents, can be explained by considering the
hydride migration that gives rise to zwitterionic intermediate
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Communications
push/pull nature of A1, the canonical form (a1*) must have an
important contribution in the resonance hybrid, and thus, the
hydrogen atom migration could be envisioned as a sigma-
of processes involving triple bonds. Moreover, the reactivity
of newly formed carbene complexes can be exploited in the
development of more complex cascade reactions to expand
the synthetic potential of this transformation. Herein we have
presented preliminary examples of a hydride transfer/cycliza-
tion/Dötz benzannulation cascade which leads to 5,6-dihy-
drophenantridine derivatives.
tropic rearrangement. This step is endergonic (DGA2-A1
=
23.4 kcalmolÀ1), and gives rise to highly unstable zwitterionic
intermediate A2. Then, after a conformational interconver-
sion into A3, cyclization through an almost barrierless process
(DGact = 2.1 kcalmolÀ1) gives rise to dihydroquinoline A4
with regeneration of the Fischer carbene complex moiety. The
overall process is exergonic (DGA4-A1 = À12.9 kcalmolÀ1).
Notably, the 1,2-dihydroquinolines (2) obtained through
the hydride transfer/cyclization processes are new alkenyl
Fischer carbene complexes. Taking into account the synthetic
versatility of Fischer carbene complexes, which can be
transformed through a myriad of different reactions,[10] this
cascade cyclization offers the opportunity to manipulate the
1,2-dihydroquinolines to introduce different functionalities or
incorporate more complex cyclic systems.
Experimental Section
General procedure for the synthesis of 1,2-dihydroquinolinyl carbene
complexes 2: A solution of alkynyl carbene complex 1 (0.5 mmol) in
THF (8 mL) was heated to 908C in a sealed tube under an argon
atmosphere until the TLC analysis showed the completion of the
reaction (the solution becomes dark violet). The mixture was then
cooled to room temperature after which it was diluted with hexanes
(10 mL) and filtered through a pad of Celite. Removal of the solvent
under reduced pressure afforded carbene complex 2 as a violet solid.
The crude complex was purified by column chromatography on silica
gel.
We explored the possibility of developing more sophisti-
cated cascade processes starting from the initial alkynyl
carbene complex. Thus, the isomerization of the Fischer
carbene complexes (1) was promoted in the presence of
alkynes. When a solution of alkynyl carbene complex 1b in
THF was heated at 908C in the presence of 4 equivalents of
1-hexyne, the reaction gave rise to 5,6-dihydrophenantridine
derivative 3a (Table 2). The structure of 3a was determined
by NMR techniques and confirmed by X-ray crystallographic
analysis.[11] These conditions were used for other carbene
complexes and both terminal and internal alkynes (Table 2).
General procedure for the synthesis of 5,6-dihydrophenantridines
3: The procedure is identical to that described above but in the
presence of alkyne (2 mmol) in THF (10 mL). The crude mixture was
purified by column chromatography on silica gel.
Received: May 15, 2008
Published online: July 24, 2008
Keywords: annulations · carbenes · chromium · heterocycles ·
.
hydrides
[1] a) W. Verboom, D. N. Reinhoudt, R. Visser, S. Harkema, J.Org.
Chem. 1984, 49, 269 – 276; b) W. N. H. Nijhuis, W. Verboom,
Table 2: Synthesis of 5,6-dihydrophenantridines (3) by
transfer/cyclization/Dꢀtz benzannulation cascade process.
a
hydride
D. N. Reinhoudt, S. Harkema, J.Am.Chem.Soc.
1987, 109,
3136 – 3138. For review, see: c) P. Mµtyus, O. Éliµs, P.
a
Tapolcsµnyi, A. Polonka-Balint, B. Halµsz-Dajka, Synthesis
2006, 2625 – 2639.
[2] a) O. Meth-Cohn, H. Suschitzky, Adv.Heterocycl.Chem. 1972,
14, 211 – 278; b) O. Meth-Cohn, Adv.Heterocycl.Chem. 1996,
65, 1 – 37.
[3] a) S. J. Pastine, K. M. McQuaid, D. Sames, J.Am.Chem.Soc.
2005, 127, 12180 – 12181; b) S. J. Pastine, D. Sames, Org.Lett.
2005, 7, 5429 – 5431.
[4] a) T. Shimada, I. Nakamura, Y. Yamamoto, J.Am.Chem.Soc.
2004, 126, 10546 – 10547; b) I. Nakamura, Y. Mizushima, Y.
Entry
1
R1
R2
R3
R4
R5
3
Yield [%]
72
1
2
3
4
1b Ph
1b Ph
1e
1e
Ph
Ph
Me Bu
Me TMS
H
H
H
H
H
Et
3a
3b 63
3c 42
3d 60
Yamamoto, J.Am.Chem.Soc.
Fürstner, P. W. Davies, J.Am.Chem.Soc.
2005, 127, 15022 – 15023; c) A.
2005, 127, 15024 –
4-Tol 4-Tol
4-Tol 4-Tol
CH2OMe
Et
15025; d) I. Nakamura, U. Yamagishi, D. Song, S. Konta, Y.
Yamamoto, Angew.Chem. 2007, 119, 2334 – 2337; Angew.Chem.
Int.Ed. 2007, 46, 2284 – 2287; e) G. Li, X. Huang, L. Zhang,
Angew.Chem. 2008, 120, 352 – 355; Angew.Chem.Int.Ed.Engl.
2008, 47, 346 – 349.
TMS=trimethylsilyl.
The formation of the 5,6-dihydrophenantridines (3) can
be explained by a sequential process in which quinolinyl
carbene complex 2, formed in the hydride transfer/cyclization
reaction, participates in a subsequent Dötz benzannulation[12]
reaction with the alkyne. From a synthetic point of view, this is
a remarkable transformation that provides complex hetero-
cyclic structures from readily available materials in a single
step.
In conclusion, we have described a novel [1,5]-hydride
transfer/cyclization process of alkynyl Fischer carbene com-
plexes which leads to 1,2-dihydroquinolynyl carbene com-
plexes. This reaction represents the first example of this type
[5] a) J. Barluenga, P. García-García, D. de Sµa, M. A. Fernµndez-
Rodriguez, R. Bernardo de La Rffla, A. Ballesteros, E. Aguilar,
M. Tomµs, Angew.Chem. 2007, 119, 2664 – 2666; Angew.Chem.
Int.Ed.Engl. 2007, 46, 2610 – 2612; b) J. Barluenga, F. Andina, F.
Aznar, C. ValdØs, Org.Lett. 2007, 9, 4143 – 4146; c) J. Barluenga,
M. Faæanµs-Mastral, M. A. Palomero, F. Aznar. C. ValdØs,
Chem.Eur.J. 2007, 13, 7682 – 7700, and references therein.
[6] Experimental details on the syntheses of the carbenes (1) are
provided on the Supporting Information.
[7] DFTcomputational calculations were carried out by employing
the B3LYP functional. Geometry optimizations were carried out
by employing the 6-31G* basis set for C, H, N, and O, and the
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Angewandte
Chemie
LANL2DZ ECP for Cr. Single-point energy calculations on the
optimized structures were conducted by employing the 6-31 + +
G** basis set for the C, H, N, and O and LANL2DZ for Cr. See
the Supporting Information for details.
[10] For recent reviews, see a) J. Barluenga, M. Tomµs, J. Santamaría,
Chem.Rev. 2004, 104, 2259 – 2283; b) Metal Carbenes in Organic
Synthesis Topics Organomet.Chem.Vol.13 (Ed.: K. H. Dötz),
Springer, Berlin, 2004; c) J. Barluenga, M. A. Fernµndez-Rodri-
guez, E. Aguilar, J.Organomet.Chem.
2005, 690, 539 – 587;
[8] For recent examples of DFTcalculations on Fischer carbene
complexes, see: a) T. Sordo, P. Campomanes, A. DiØguez, F.
Rodríguez, F. J. Faæanµs, J.Am.Chem.Soc. 2005, 127, 944 – 952;
b) I. Fernµndez, M. A. Sierra, F. P. Cossio, J.Org.Chem. 2008,
73, 2083 – 2089.
[9] Four different conformers, very close in energy, were found for
the transition state of the migration of a benzylic hydrogen atom.
Only the lowest energy structure, TS(A1–A2), was considered.
Moreover, the transition state for the migration of a hydrogen
atom from the methyl group, not observed experimentally,
featured a Gibbs free energy value that was 3.4 kcalmolÀ1 higher
than that for TS(A1–A2).
d) Y.-T. Wu, T. Kurahashi, A. de Meijere, J.Organomet.Chem.
2005, 690, 5900 – 5911; e) J. W. Herndon, Coord.Chem.Rev.
2006, 250, 1889 – 1964.
[11] CCDC 687236 (3a) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[12] a) K. H. Dötz, Angew.Chem. 1975, 87, 672 – 673; Angew.Chem.
Int.Ed.Engl.
1975, 14, 644 – 645. For general reviews, see:
b) K. H. Dötz, P. Tomuschat,Chem.Soc.Rev. 1999, 28, 187 – 198;
c) A. Minatti, K. H. Dötz, Metal Carbenes in Organic Synthesis
(Ed.: K. H. Dötz), Springer, New York, 2004, pp. 123 – 156.
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