Pd-Catalyzed Hydroamination of Alkoxyallenes with Azole Heterocycles: Examples and Mechanistic Proposal

Article abstract of DOI:10.1021/acs.orglett.7b01826

Palladium-catalyzed regio- and enantioselective addition of azole heterocycles to alkoxyallenes was developed (up to 92% yields and up to 94% ee). DFT calculations suggest a new Pd(0)-driven mechanistic pathway proceeding through protonation of the Pd-coo

Full text of DOI:10.1021/acs.orglett.7b01826

Letter
pubs.acs.org/OrgLett
Pd-Catalyzed Hydroamination of Alkoxyallenes with Azole
Heterocycles: Examples and Mechanistic Proposal
Ivan Bernar,† Bela Fiser,‡,§ Daniel Blanco-Ania,† Enrique Gomez-Bengoa,*,‡ and Floris P. J. T. Rutjes*,†
́
́
†Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
‡Department of Organic Chemistry I, University of the Basque Country (UPV/EHU), P.O. Box 1072, 20080 Donostia-San Sebastian
Spain
́
,
§Institute of Chemistry, Faculty of Materials Science and Engineering, University of Miskolc, H-3515, Egyetemvar
Hungary
́
os-Miskolc,
S
* Supporting Information
ABSTRACT: Palladium-catalyzed regio- and enantioselective
addition of azole heterocycles to alkoxyallenes was developed (up
to 92% yields and up to 94% ee). DFT calculations suggest a new
Pd(0)-driven mechanistic pathway proceeding through protonation
of the Pd-coordinated allene (4-PdL2), which develops a strongly
nucleophilic character at the central C atom.
a
Table 1. Reaction Optimization
he palladium-catalyzed addition of nitrogen nucleophiles
T
to alkoxyallenes is a straightforward conversion to form
the corresponding allylic N,O-acetals under mildly basic
conditions.1 These reactive structures have been used as key
intermediates in the synthesis of biologically active heterocycles
and natural products.2 Examples from our group include the
stereoselective synthesis of the natural product L-baikiain2b and
a formal total synthesis of the alkaloid quinolizidine 233A.2c,3
To follow up on these results, we envisioned that also aromatic
nitrogen nucleophiles, so-called azole heterocycles, would be of
particular interest as reactants in such hydroaminations. Thus,
we explored the potential of catalytic and enantioselective
reactions at the azole nitrogen to gain access to a broad range of
chiral, heteroaromatic allylic N,O-acetals 3. Additionally, while
palladium hydride species have been invoked as reactive
intermediates in most of the hydroamination studies,4,5 our
current computational investigations argue against such
intermediates. We present herewith DFT calculations that
suggest an alternative mechanistic pathway that proceeds via
coordination of the allene to Pd(0), and protonation with
imidazole of the resulting 4-PdL2 species at the central carbon
atom (TS-1). Initial studies to synthesize heteroaromatic allylic
N,O-acetals were guided by previous work from our laboratory
on palladium-catalyzed addition of nitrogen nucleophiles to
alkoxyallenes. Imidazole (2a) and benzyloxyallene (1a) were
used for optimizing the reaction conditions (Table 1).
Gratifyingly, the first attempt in the presence of a catalytic
amount of Pd(OAc)2/dppp (1,3-bis(diphenylphosphino) pro-
pane) in refluxing THF provided the desired product 3a in 82%
yield as a single regioisomer (entry 1). Similar results were
b
entry
base
catalyst
yield (%)
1
2
3
DBU
DBU
DBU
DBU
DBU
Pd(OAc)2/dppp
Pd2(dba)3/dppp
Pd(PPh3)4
82
87
85
62
78
93
c
4
Pd2(dba)3/dppp
Pd2(dba)3/dppp
Pd2(dba)3/dppp
d
5
6
a
Conditions: Pd catalyst (5 mol %), dppp (5 mol %), 1a (0.3 mmol),
b
c
2a (0.36 mmol), THF (3.0 mL), 60 °C, 12 h. Isolated yield. 23 °C.
d
MeCN, reflux.
obtained by changing catalyst, temperature, and solvent (entries
2−5). Unexpectedly, in the absence of additional base and
under the optimal reaction conditions (2.5 mol % of Pd2dba3,
5.0 mol % of dppp in THF) the reaction went to completion in
4 h at 60 °C, yielding the desired N,O-acetal 3a in 93% yield
(entry 6).
Along with these results, different heterocyclic systems
containing the azole framework were subjected to the
Received: June 15, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01826
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Organic Letters
Letter
a,b
Scheme 1. Scope of Pd(0)-Catalyzed Allylic N,O-Acetal Formation
a
b
c
Conditions: Pd2(dba)3 (2.5 mol %), dppp (5 mol %), 1 (0.3 mmol), 2 (0.36 mmol), THF (3.0 mL), 60 °C was used. Isolated yields. Carried out
d
e
on a 1 mmol scale. (R,R)-L1 (5 mol %) was used as ligand, DCE (3.0 mL). The ee values were determined by HPLC analysis.
optimized reaction conditions (Scheme 1A). Generally, the
anticipated N,O-acetals 3a−w were obtained in modest to
excellent yields (54−92%). In the case of asymmetrically
substituted imidazoles, mixtures of the 4- and 5-substituted
isomers 3e−h were obtained. Thus, 4-nitroimidazole and
imidazole-4-carbaldehyde were converted into C-4 allylic N,O-
acetals 3e and 3f in good yields with nearly complete
regioselectivity. In contrast, 4-methylimidazole and 4-iodoimi-
dazole showed almost no regioselectivity, yielding a close to 1:1
mixture of the 4- and 5-substituted isomers 3g and 3h.
Remarkably, in the case of pyrrole, only degradation of allene
1a was observed.6 Changing the conditions (solvent, temper-
ature, Pd catalysts, addition of base) did not lead to product 3i
either. In contrast, pyrroles substituted with electron-with-
drawing groups, in particular, pyrrole-2-carbaldehyde and
pyrrole-2-carbonitrile, showed nearly the same reaction rates
as imidazole and gave the desired products in good yields (72
and 83% for 3j and 3k, respectively). Azole heterocycles with
multiple N-nucleophilic centers also showed good reactivity in
the intermolecular addition to benzyloxyallene (1a). To our
delight, the corresponding triazole-containing N,O-acetals 3o,p
were obtained in good to excellent yields and excellent
regioselectivities. Likewise, when bulky substrates such as
theophylline and 2-bromotheophylline were used, the corre-
sponding N,O-acetals 3q and 3r were formed with good
selectivity.
Next, we examined the asymmetric version of Pd-catalyzed
hydroamination of imidazole (2a) with a variety of
alkoxyallenes (Scheme 1B). Here, we evaluated several
commercially available chiral bisphosphine ligands, solvents,
and additives (for detailed information on the optimization, see
the Supporting Information). Our strategy was based on the
work on Pd- and Rh-catalyzed asymmetric additions onto
allenes.5 In analogy to this work, Rhee et al. recently reported
several successful examples of Pd-catalyzed asymmetric hydro-
aminations, which opened up a route toward enantioselective
allylic N,O-acetal formation.1e−g,2d,e Modifying their procedure
and performing the reaction in the presence of Pd2(dba)3 (2.5
mol %) and (R,R)-DACH-naphthyl Trost ligand L1 (5 mol %),
we were pleased to observe that a number of alkoxyallene
analogues reacted well with imidazole giving rise to products
(S)-3s−w and (S)-3a, not only in good yields but in most cases
also with high enantioselectivities (up to 94% ee).
To indicate the broader scope and reveal the absolute
configuration of the obtained products, we performed the
reaction with 1,3-dimethylxantine theophylline and allene (1a),
and the crystal structure of the major enantiomer of product 3q
(74%, 92% ee) was elucidated. The absolute configuration was
assigned to be S in all cases based on the X-ray data of 3q and
B
DOI: 10.1021/acs.orglett.7b01826
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Organic Letters
Letter
the CD profiles of the other products (see the SI), which is in
correspondence with the expected stereochemistry.
However, some critical inconsistencies were evidenced
around the participation of intermediate 7 in the mechanism
(Scheme 2) since its existence was incompatible with the
following data: (a) A determining preference of 18.9 kcal/mol
for the coordination of Pd(0) to allene 1a over imidazole (2a)
was found (10a vs 9, Figure 1), severely compromising any
further participation of palladium species 9 and TS-3 in the
mechanism of the reaction.8 (b) The formation of H−Pd+ X−
species of type 7 has been exclusively described for strong H−X
acids, and the hydride has not been observed when weaker
acids were used.9 In agreement with these experimental facts,
the computed equilibrium between Pd(0) and trifluoroacetic
acid is shifted toward the formation of cationic H−Pd+ species
7 by 4.8 kcal/mol (Scheme 2), while using imidazole as a
proton source, the hydride is disfavored by 22.5 kcal/mol. (c)
The combination of factors a and b affords an unrealistic energy
of 41.1 kcal/mol for hydride 7 over 10a, and even the
formation of other less unstable Pd−H species (e.g., 12, see SI)
is unreachable by any means (Figure 1).10 We can safely state
that in these conditions, H−Pd+ species would never form.
Therefore, the intriguing findings that intermediates 10a and 8
participate in the mechanism but are at the same time not
connected through the cationic H−Pd+ species 7 led us to
search for a pathway to connect both intermediates. Gratify-
ingly, after some computational effort, a new transition state
(TS-1) was located for the direct protonation of the Pd-
coordinated allene with imidazole with a moderate activation
barrier of 19.7 kcal/mol (Figure 1).11 The structure is highly
interesting and original and implies that the allene, after
coordination to Pd(0) in 10a, becomes sufficiently basic at the
central C atom to deprotonate imidazole.
The mechanism of the Pd-catalyzed additions of pronucleo-
philes with relatively acidic protons to allenes has been
thoroughly investigated by Trost.5 Experimental studies have
shown that this process is initiated by oxidative addition of
palladium into the acidic C−H bond to form a cationic Pd−H
species (7, Scheme 2). This intermediate can readily react with
a
Scheme 2. Classical Mechanism of the Hydroamination
a
Free energies (298 K) with respect to 6 are shown in kcal/mol.
the allene, thereby generating a π-allylpalladium species (8).
Addition of the anion of the pronucleophile to this intermediate
through trajectories a or b then forms the products with
regeneration of the Pd(0) catalyst.
Since no studies have been reported on the protonation of
low-valent palladium with weak acids (e.g., imidazole), we
turned to DFT calculations7 to shed light on a plausible
mechanism for our alkoxyallene/imidazole reaction and
considered initially a pathway similar to that outlined in
Scheme 2. Indeed, our preliminary calculations showed that 8
(X = imidazolide, L2 = 1,3-bis(dimethylphosphino) propane,
dmpp) is a reasonable intermediate for the reaction. Its
computed free energy value was 5.6 kcal/mol lower than the
sum of the initial substrates (6 + imidazole + allene 1a, Scheme
2), and its reaction with the imidazolide nucleophile
preferentially occurs through the a trajectory (8.0 kcal/mol
lower than b) to form the N,O-acetal product, in agreement
with the experimental findings.
Indeed, a very high-in-energy local minimum structure (11,
19.1 kcal/mol higher than 10a) was located during the intrinsic
reaction coordinate (IRC) of the transition state TS-1,
corresponding to a bidentate coordination mode of allene to
palladium with high nucleophilic carbene character.12 The
carbene-like species 11 is so close in energy (ΔΔG⧧ = 0.6 kcal/
Figure 1. Computed reaction pathway with 3-D representation of the HOMO orbitals for 11. Free energies (298 K) with respect to starting
materials are shown in kcal/mol.
C
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Letter
Hiemstra, H.; Rutjes, F. P. J. T. J. Org. Chem. 2005, 70, 5519.
(c) Donohoe, T. J.; Orr, A. J.; Gosby, K.; Bingham, M. Eur. J. Org.
Chem. 2005, 2005, 1969. (d) Donohoe, T. J.; Kershaw, N. M.; Orr, A.
J.; Wheelhouse, K. M. P.; Fishlock, L. P.; Lacy, A. R.; Bingham, M.;
Procopiou, P. A. Tetrahedron 2008, 64, 809. (e) Kim, H.; Rhee, Y. H.
Synlett 2012, 23, 2875. (f) Kim, H.; Rhee, Y. H. J. Am. Chem. Soc.
2012, 134, 4011. (g) Kim, H.; Lim, W.; Im, D.; Kim, D.; Rhee, Y. H.
Angew. Chem., Int. Ed. 2012, 51, 12055. (h) Zimmer, R.; Reissig, H.-U.
Chem. Soc. Rev. 2014, 43, 2888.
(2) For allylic N,O-acetals as key intermediates in synthesis of some
natural compounds: (a) Tjen, K. C. M. F.; Kinderman, S. S.;
Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T. Chem. Commun.
2000, 699. (b) Kinderman, S. S.; Doodeman, R.; van Beijma, J. W.;
Russcher, J. C.; Tjen, K. C. M. F.; Kooistra, T. M.; Mohaselzadeh, H.;
van Maarseveen, J. H.; Hiemstra, H.; Schoemaker, H. E.; Rutjes, F. P. J.
T. Adv. Synth. Catal. 2002, 344, 736. (c) Kinderman, S. S.; de Gelder,
R.; van Maarseveen, J. H.; Schoemaker, H. E.; Hiemstra, H.; Rutjes, F.
P. J. T. J. Am. Chem. Soc. 2004, 126, 4100. (d) Kang, S.; Kim, D.; Rhee,
Y. H. Chem. - Eur. J. 2014, 20, 16391. (e) Lim, W.; Rhee, Y. H.
Tetrahedron 2015, 71, 5939.
mol) to the transition state that it could not be considered a
stable reaction intermediate, but it is still very informative,
revealing that during the protonation trajectory from 10a to
TS-1, the allene bends and develops a significant negative
charge at the central C atom.13 Finally, the attack of the
imidazolide to 8 was found to occur through pathway a, as in
Scheme 2 (TS-2a, Figure 1), with an activation free energy of
11.3 kcal/mol.
In conclusion, we have developed highly effective Pd-
catalyzed protocols for the addition of a wide scope of azole
heterocycles to alkoxyallenes providing a unique way to
synthesize aromatic allylic N,O-acetals in high yields (up to
95%) and enantiomeric excesses (up to 94%). A nonconven-
tional Pd(0)-driven mechanistic pathway was proposed based
on the DFT calculations of the studied process. This should be
considered as an alternative pathway for nonacidic nucleophiles,
where highly favorable coordination of allene to the palladium
catalyst followed by the protonation with a week acid forms
Pd−π-allyl species. Such a process involves a reactive, carbene-
like local minimum, which is a crucial link that connects both
intermediates. At the same time, acidic nucleophiles, as well as
acid/base additives, would rather prefer to form the Pd−π-allyl
complex through cationic Pd−H species. Further studies on
trapping the reaction intermediates and understanding the
mechanism of this reaction, as well as the application of this
methodology in target-orientated synthesis, are currently in
progress.
(3) Michael, J. P. Nat. Prod. Rep. 2002, 19, 719.
(4) For the mechanism of palladium-catalyzed additions of
pronucleophiles to allenes, see: (a) Besson, L.; Gore, J.; Cazes, B.
́
Tetrahedron Lett. 1995, 36, 3857. (b) Yamamoto, Y.; Al-Masum, M.;
Asao, N. J. Am. Chem. Soc. 1994, 116, 6019. (c) Yamamoto, Y.;
Radhakrishnan, U. Chem. Soc. Rev. 1999, 28, 199. (d) Kamijo, S.;
Yamamoto, Y. Tetrahedron Lett. 1999, 40, 1747.
(5) Selected examples of Pd- and Rh-catalyzed asymmetric additions
onto allenes: (a) Trost, B. M.; Jakel, C.; Plietker, B. J. Am. Chem. Soc.
̈
2003, 125, 4438. (b) Trost, B. M.; Simas, A. B. C.; Plietker, B.; Jakel,
̈
C.; Xie, J. Chem. - Eur. J. 2005, 11, 7075. (c) Trost, B. M.; Xie, J.;
Sieber, D. J. Am. Chem. Soc. 2011, 133, 20611. (d) Koschker, P.; Breit,
B. Acc. Chem. Res. 2016, 49, 1524. (e) Thieme, N.; Breit, B. Angew.
Chem., Int. Ed. 2017, 56, 1520.
(6) (3,3-Bis(benzyloxy)prop-1-ene was formed as the major product.
This side product is presumably formed after partial degradation of
benzyloxyallene 1a followed by addition of released BnOH to 1a. For
similar results see ref 5b.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01826.
■
S
Experimental procedures, spectroscopic characteriza-
tions, crystallographic analyses (CIF), and computational
data(PDF)
General methods, complex formation, and Cartesian
coordinates (PDF)
(7) M06/6-311+G**(SDD) level of theory was used in all cases, and
for verification purposes, other theoretical levels were applied when
necessary.
(8) Species 7 and 10a are the most stable structures among a series of
isomeric Pd(0) complexes with imidazole and allene. The rest of the
structures can be found in the Supporting Information.
(9) Hydrido complexes of palladium as key intermediates in the
process: (a) Leoni, P.; Sommovigo, M.; Pasquali, M.; Midollini, S.;
Braga, D.; Sabatino, P. Organometallics 1991, 10, 1038. (b) Grushin, V.
V. Chem. Rev. 1996, 96, 2011. (c) Trost, B. M. Chem. - Eur. J. 1998, 4,
2405. (d) Amatore, C.; Jutand, A.; Meyer, G.; Carelli, I.; Chiarotto, I.
Eur. J. Inorg. Chem. 2000, 2000, 1855.
X-ray data for compound (S)-3q (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: enrique.gomez@ehu.es (computational part).
*E-mail: floris.rutjes@ru.nl (experimental part).
Notes
(10) Other different Pd(II) hydride species (e.g., imidazolide-Pd−H)
were also considered, and can be found in the Supporting Information.
None of them is operative.
The authors declare no competing financial interest.
(11) Different computational levels show consistent activation energy
values for TS-1: M06/6-311+G**(SDD): 19.7 kcal/mol; M06/
def2TZVPP: 19.0 kcal/mol; B3LYP-D3/6-31G**(LANL2DZ): 17.8
kcal/mol. CPCM-MeCN solvent model was used in all cases.
(12) For comparative Fukui nucleophilicity indexes and HOMO
energies of 10a and 11, see the Supporting Information.
(13) The exact nature of structure 11, which could be a local
minimum computational artifact along the reaction trajectory, does not
compromise the low activation energy from 10a to TS-1. At some
point during the formation of TS-1, the allene−Pd system should
reorganize as in 11.
ACKNOWLEDGMENTS
■
Financial support for this research was provided by the
FP7Marie Curie Actions of the European Commission via
the ITN ECHONET (MCITN-2012-316379). We also
acknowledge technical and human support provided by IZO-
SGI SGIker of UPV-EHU. Prof. Dr. B. de Bruin and Dr. J. C.
Slootweg (University of Amsterdam) are kindly acknowledged
for useful suggestions.
REFERENCES
■
(1) Selected reports of palladium-catalyzed additions of N-
nucleophiles to alkoxyallenes of general formula 4: (a) Desarbre, E.;
Merour, J. Y. Tetrahedron Lett. 1996, 37, 43. (b) Kinderman, S. S.;
Wekking, M. M. T.; van Maarseveen, J. H.; Schoemaker, H. E.;
D
DOI: 10.1021/acs.orglett.7b01826
Org. Lett. XXXX, XXX, XXX−XXX