Mild and Functional Group Tolerant Method for Tandem Palladium-Catalyzed Carbocyclization-Coupling of ?-Acetylenic β-Ketoesters with Aryl Bromides and Chlorides

Article abstract of DOI:10.1002/adsc.201600175

We report a new protocol for the annulative difunctionalization of acetylenes via tandem carbocyclization-coupling of ?-acetylenic β-ketoesters with aryl and heteroaryl bromides and chlorides catalyzed by the palladium species derived from an air- and moisture-stable palladacyclic precatalyst. In the tandem process, the palladium complex combines appropriate carbophilic Lewis acidity and redox activity to catalyze two mechanistically distinct reactions - nucleophilic addition of the enolate to unactivated alkyne, followed by C-C coupling. We found that a broad range of electronically varied aryl and heteroaryl bromides and chlorides underwent this reaction with various ?-acetylenic β-ketoesters, providing corresponding substituted vinylidenecyclopentanes in high yield with excellent functional group tolerance.

Full text of DOI:10.1002/adsc.201600175

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DOI: 10.1002/adsc.201600175
Mild and Functional Group Tolerant Method for Tandem Palladi-
um-Catalyzed Carbocyclization–Coupling of e-Acetylenic b-Ke-
toesters with Aryl Bromides and Chlorides
a,
a
´
Wojciech Chaładaj * and Sylwester Domanski
a
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Fax: +48 22 632 66 81, Phone: +48 22 343 21 25; e-mail: wojciech.chaladaj@icho.edu.pl
Received: February 10, 2016; Revised: March 25, 2016; Published online: April 27, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600175.
Abstract: We report a new protocol for the annula-
We found that a broad range of electronically
tive difunctionalization of acetylenes via tandem car- varied aryl and heteroaryl bromides and chlorides
bocyclization–coupling of e-acetylenic b-ketoesters underwent this reaction with various e-acetylenic b-
with aryl and heteroaryl bromides and chlorides cat- ketoesters, providing corresponding substituted vi-
alyzed by the palladium species derived from an air- nylidenecyclopentanes in high yield with excellent
and moisture-stable palladacyclic precatalyst. In the functional group tolerance.
tandem process, the palladium complex combines ap-
propriate carbophilic Lewis acidity and redox activi-
ty to catalyze two mechanistically distinct reactions -
nucleophilic addition of the enolate to unactivated Keywords: carbocyclization; cross-coupling; homoge-
À
alkyne, followed by C C coupling.
neous catalysis; palladium; tandem reactions
Introduction
Although a handful of successful protocols employ-
ing organogold intermediates for C Au bond func-
À
Catalytic carbophilic activation of alkynes towards tionalization have been reported,[2] palladium, which
nucleophilic addition by p-acidic metal complexes combines redox activity with carbophilic p-acidity, is
serves as the foundation for numerous powerful now recognized as the metal of choice for this type of
atom-economic transformations. In the past two de- transformation. In fact, a number of tandem palladi-
cades this field was dominated by gold complexes, um catalyzed double functionalizations of alkynes
due to their remarkable activity, insensitivity to air have been reported.[3] The vast majority of the report-
and moisture, and functional group compatibility.[1] ed protocols utilize ligandless or arylphosphine ligat-
The organometallic intermediate formed in the cata- ed palladium species as a catalyst, resulting in
lytic cycle typically undergoes proto-demetallation, a narrow scope in respect to aryl halide. In a few
liberating product and regenerating the catalytically recent reports, however, palladium complexes with
active metal complex. However, harnessing the reac- bulky electron rich phosphine ligands have been
tivity of the organometallic intermediate would open shown to be active catalysts of tandem cyclization–
À
up the possibility of further C M bond functionaliza- coupling reactions of alkynes, accepting various aryl
tion (Scheme 1).
bromides as electrophiles.[4]
In the early 1990s, Gore[5] showed that palladium
dppe complex is able to catalyze tandem carbocycliza-
tion–coupling of e-acetylenic b-ketoesters with aryl io-
dides (Scheme 2).[6] Although the reported protocol
enables the reaction to proceed in high yields at rela-
tively low temperature, it involves several constraints:
high catalyst loading and the use of a strong base are
required, and the scope with respect to electrophiles
is limited to aryl iodides. Nevertheless, the approach
has the immense advantages of atom efficiency and
À
Scheme 1. Protodemetallation vs C M functionalization of
vinylmetal intermediate.
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and base used, catalyst loading, concentration and re-
agent ratio.[11] Catalyst derived from XPhos was found
to lead to the best results (up to 80% yield), even at
such low catalyst loading as 0.5 mol% and with
a nearly equimolar ratio of ketone, bromobenzene
and base, when a combination of polar aprotic solvent
with relatively weak inorganic bases, such as Cs2CO3,
K2CO3 or K3PO4 was used. To render the procedure
more practical, commercially available palladacyclic
pre-catalysts[12] were tested and proved to perform
similarly to or better than in-situ prepared catalysts.
Having identified an active catalyst and satisfactory
conditions, we found that a wide range of electroni-
cally and structurally varied aryl, heteroaryl and vinyl
bromides underwent the reaction in high yields
(Table 1). Ketoester 1, as a more elaborate substrate,
was generally used as a limiting reagent (Conditions
A), but for comparison, several examples with bro-
moarene as a limiting reagent (Conditions B) were re-
ported. In most cases the Z isomer was obtained ex-
clusively, except for reactions run with electron defi-
Scheme 2. Synthetic routes to exo-arylmethylene cyclopen-
tanes via cyclization of e-acetylenic b-ketoesters.
rapid buildup of molecular complexity. Thereby, over- cient bromoarenes when the formation of small
coming the aforementioned difficulties, especially ex- amounts (<10%) of other isomers was noticed (3–5,
tending the scope of application to a wide range of 25, 26).
aryl bromides, would open up a route to a powerful
synthetic tool.
A variety of functionalities, including cyano (3),
ether (7, 8), ester (15, 16), olefin (14), enolizable
This type of structural motif can potentially be ach- ketone (5), amide (18), carbamate (19), sulfonamide
ieved by Conia-ene reaction of more elaborate inter- (20) as well as free amine (9) and hydroxy (10–13)
nal e-acetylenic b-ketoesters (Scheme 2).[7] Steric con- groups are well tolerated. The scope of the reaction
straints, however, pose a serious challenge to this ap- also covers a rage of brominated heterocyclic partners
proach, resulting in a lack of corresponding protocols. (21–31), including nitrogen-containing heterocycles
Although Balme[8] developed an efficient procedure (23–30) – moieties of particular importance for medic-
for copper Conia-ene cyclization of internal alkynes inal chemistry. Furthermore, it was shown that vinyl
cleanly in 5-exo-dig fashion, it requires microwave bromides are also compatible with the reaction condi-
heating to 1508C and the use of a strong base (CaH2). tions, leading to corresponding dienes (32–33) in good
Alternatively, gold complexes with Sawamuraꢁs[9] yields.
bulky semihollow ligand (molecular weight>3000!)
Next, the scope in respect to ketoester partners was
enable efficient reaction of nonterminal alkynic b-ke- investigated. Structurally varied ketoesters successful-
toesters, but an inseparable mixture of 5-exo-dig and ly underwent the reactions with selected electronically
6-endo-dig cyclization products is formed.
diverse bromoarenes (Table 2). In general, sterically
Herein, we report an efficient protocol for a palladi- more demanding substrates required higher reaction
um catalyzed tandem carbocyclization–coupling of e- temperature to assure good efficiency of the process.
acetylenic b-ketoesters with aryl and heteroaryl bro-
Homologues of 1, differing in the length of the
mides and chlorides. The reaction occurs with low tether between the ketoester and acetylenic moieties,
loading of air- and moisture-stable, commercially
available pre-catalyst (XPhos Pd G3) and under mild
conditions compatible with a wide range of functional
groups, including heterocycles of potentially great im-
portance for medicinal chemistry.[10]
Results and Discussion
We began by evaluating a model reaction of methyl
2-acetylhept-6-ynoate
(1.5 equiv) against a series of palladium catalysts as
well as a range of reaction parameters, such as solvent er 1.
(1)
with
bromobenzene
Scheme 3. Reactions with homologues of acetylenic ketoest-
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Table 1. Substrate scope: aryl bromides.[a]
Table 2. Substrate scope: acetylenic b-ketoesters.[a]
[a]
[b]
2-acetylhept-6-ynoate (0.400 mmol), aryl bromide
(0.44 mmol), K3PO4 (0.44 mmol), XPhos Pd G3 (2.0
mmol), DMF (1 mL), 50–808C, 2-18 h.
K2CO3 was used. Isolated as a mixture of isomers
(79:11:5:5).
sluggish. Nonetheless the expected product 42 was ob-
tained in moderate yield (54%), although higher cata-
lyst loading and longer reaction time was required.
Cyclization of the shorter homologue 43, on the other
hand, proceeded smoothly under normal conditions,
although it led a corresponding oxo-cyclization–cou-
pling product 44. Such reaction modes lie in parallel
with Baldwinꢁs rules[13] allowing for 6-exo-dig. Inter-
estingly, no 5-endo-dig cyclization was observed, con-
trary to the reported gold[14,15] and palladium[6] cata-
lyzed cyclizations of dicarbonyl compounds tethered
to alkynes.
[a]
Conditions A: 2-acetylhept-6-ynoate (0.400 mmol), aryl
bromide (0.44 mmol), K3PO4 (0.44 mmol), XPhos Pd G3
(2.0 mmol), DMF (1 mL), 508C, 2 h; Conditions B: 2-ace-
tylhept-6-ynoate (0.6 mmol), aryl bromide (0.400 mmol),
K3PO4 (0.6 mmol), XPhos Pd G3 (2.0 mmol), DMF
(1 mL), 508C, 2 h.
[b]
1 mol% of XPhos Pd G3 was used.
run at 808C.
[c]
The scope of the reaction also encompasses aryl
were also tested in the reaction (Scheme 3). As ex- chlorides (considerably less active electrophiles), al-
pected, 6-exo-dig cyclization-coupling of 41 was more though slightly more forceful conditions (808C,
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1 mol% of catalyst, 1.5 equiv of ArCl) were required.
In reactions of a series of electronically varied chloro-
arenes with selected acetylenic ketoesters, the expect-
ed products were obtained in yields comparable to
the analogous reactions employing bromoarenes
(Table 3).
Table 3. Substrate scope: aryl chlorides.[a]
Scheme 5. Plausible mechanism. OA - oxidative addition,
RE - reductive elimination, NA - nucleophilic addition.
A plausible mechanism is depicted in Scheme 5.
Pd(II) intermediate 50, formed via oxidative addition
of aryl bromide to Pd(0) species 49, activates alkyne
through p-coordination, producing 51. Then the base
triggers 5-exo-dig cyclization to form (E)-vinylpalladi-
um intermediate 52, which undergoes reductive elimi-
nation, liberating product, regenerating active Pd(0)
species 49 and thus closing the catalytic cycle. Such
[a]
2-acetylhept-6-ynoate
(0.6 mmol), K3PO4 (0.44 mmol), XPhos Pd G3 (4.0
mmol), DMF (1 mL), 808C, 2 h.
(0.400 mmol),
aryl
chloride
[b]
reaction time 4 h.
The products of the carbocyclization–coupling reac- a pathway is strongly supported by stereochemical
tion are valuable building blocks, bearing various outcome of the reaction and is consistent with previ-
functional groups suitable for further selective manip- ous reports.[16]
ulations (Scheme 4). For instance, the carbonyl and
The postulated vinylpalladium intermediate might
olefinic groups of 2 can be selectively reduced (with undergo protodepalladation instead of reductive elim-
NaBH4 and H2/Pd/C, respectively), leaving other ination, leading to the formation of Conia-ene prod-
functionalities untouched (Scheme 4). Particularly in- uct 53, which could be considered an intermediate in
terestingly, the carbonyl group of the ketone moiety the catalytic cycle. However, independently obtained
in 2 could be readily cleaved to afford, after sponta- 53 did not undergo the Heck reaction under the
neous migration of double bond, cyclic a,b-unsaturat- normal reaction conditions.
ed ester 47 (Scheme 4). The ease of the acetyl cleav-
Seeing as oxidative additions and reductive elimina-
age makes basic hydrolysis of the ester difficult, if at tion on XPhos-Pd complexes are fast, cyclization is
all possible. However, acidic cleavage of the corre- presumably a rate-limiting step of the catalytic cycle.
sponding tert-butyl ester of 35a proceeded smoothly, A comparison experiment showed that under similar
producing free acid 48 under mild conditions reaction conditions compound 54 undergoes Negishi
(Scheme 4).
coupling much faster than 1 undergoes tandem cycli-
zation–coupling (Scheme 6). Both processes proceed
through a common intermediate 52, proving that the
reductive elimination is not a rate-limiting step.
Scheme 6. Comparison of rates of tandem cyclization–cou-
pling and coupling proceeding through a common inter-
mediate.
Scheme 4. Synthetic utility of 2.
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a 4 mL screw-capped vial was charged with XPhos Pd G3
Conclusion
(3.40 mg, 4.0 mmol), aryl chloride (0.6 mmol), K3PO4
(93.3 mg, 0.44 mmol), DMF (1 mL), and a magnetic stirring
bar. Then ketoester (0.400 mmol) was added, the vial was
sealed with a cap containing a PTFE septum and removed
from the drybox. The reaction mixture was stirred at 808C
for 2 h and then cooled to room temperature. The mixture
was quenched with NH4Cl(aq.) (20 mL) and extracted with
MTBE (3”15 mL). Combined organic extracts were dried
(Na2SO4), concentrated and crude product was purified by
column chromatography on silica gel (~17 g). The condi-
tions for chromatography and data for characterization of
the products are reported as supporting information.
In conclusion, we have developed an efficient, func-
tional group tolerant, palladium-catalyzed intramolec-
ular difunctionalization of alkynes via nucleophilic ad-
dition of b-ketoester followed by cross-coupling. In
the tandem process, palladium complex efficiently
catalyzes two mechanistically distinct reactions – nu-
cleophilic addition of the enolate to an unactivated
À
C C bond and coupling with aryl bromide. The reac-
tion accepts a wide range of aryl, heteroaryl and vinyl
bromides and chlorides and structurally diverse ke-
toesters. The mild reaction conditions, low loading of
air- and moisture-stable precatalyst and tolerance of
functionalities, including free OH, NHR or enolizable
ketones, make the reaction a valuable tool for synthe-
sis of exo-(hetero)arylmethylene cycloalkanes, includ-
ing fused ring systems. Further studies extending the
range of Pd-catalyzed tandem difunctionalizations of
alkynes are underway.
Analytical data of the representative example of the iso-
lated compounds – product of carbocyclization–coupling of
methyl 2-acetylhept-6-ynoate and bromobenzene: (E)-
methyl 1-acetyl-2-benzylidene-cyclopentanecarboxylate (2).
Prepared in reaction of methyl 2-acetylhept-6-ynoate and
bromobenzene under conditions A (yield: 80%) and condi-
tions B (yield: 91%), or in reaction of methyl 2-acetylhept-
6-ynoate and chlorobenzene under conditions C (yield:
78%). The title compound was isolated as an oil after chro-
matography on silica gel (17 g column, 95:5!90:10 hexanes/
1
EtOAc). H NMR (400 MHz, CDCl3) d 7.37–7.32 (m, 4H),
7.27–7.20 (m, 1H), 6.60 (t, J=2.5 Hz, 1H), 3.78 (s, 3H),
2.80–2.63 (m, 2H), 2.50–2.41 (m, 1H), 2.26 (s, 3H), 2.25–
2.16 (m, 1H), 1.89–1.75 (m, 2H); 13C NMR (101 MHz,
CDCl3) d 204.0, 171.8, 141.5, 137.4, 128.6, 128.2, 127.6, 126.9,
72.2, 52.6, 34.4, 32.0, 26.8, 24.8; IR (CH2Cl2): 3410, 2953,
1737, 1714, 1493, 1447, 1433, 1356, 1238, 697 cmÀ1; MS (EI),
m/z (%): 258 (7, M+), 216 (80), 184 (100), 167 (13), 155 (86),
141 (19), 128 (34), 115 (29), 105 (14), 91 (35), 77 (23), 43
(46); HRMS, m/z: calc’d for C16H18O3: 258.1256. Found
258.1255.
Experimental Section
General procedure for palladium-catalyzed
carbocyclization-coupling of e-acetylenic b-ketoesters
with aryl, heteroaryl and vinyl halides
Conditions A (for reaction of aryl, heteroaryl and vinyl bro-
mides with ketoester as a limiting reagent): In a drybox,
a 4 mL screw-capped vial was charged with XPhos Pd G3
(1.70 mg, 2.0 mmol), aryl bromide (0.44 mmol), K3PO4
(93.3 mg, 0.44 mmol), DMF (1 mL), and a magnetic stirring
bar. Then ketoester (0.400 mmol) was added, the vial was
sealed with a cap containing a PTFE septum and removed
from the drybox. The reaction mixture was stirred at 508C
for 2 h and then cooled to room temperature. The mixture
was quenched with NH4Cl(aq.) (20 mL) and extracted with
MTBE (3”15 mL). Combined organic extracts were dried
(Na2SO4), concentrated and crude product was purified by
column chromatography on silica gel (~17 g). The condi-
tions for chromatography and data for characterization of
the products are reported as supporting information.
Acknowledgements
Financial support from the Polish National Science Centre
(Grant. 2013/11/D/ST5/02979) and Polish Ministry of Science
and Higher Education (stipend for W.C.) is gratefully ac-
knowledged. The authors thank Professor Janusz Jurczak for
his help and valuable discussion.
Conditions B (for reaction with aryl and heteroaryl bro- References
mides as a limiting reagent): In a drybox, a 4 mL screw-
capped vial was charged with XPhos Pd G3 (1.70 mg, 2.0
mmol), aryl bromide (0.400 mmol), K3PO4 (93.3 mg,
0.6 mmol), DMF (1 mL), and a magnetic stirring bar. Then
ketoester (0.6 mmol) was added, the vial was sealed with
a cap containing a PTFE septum and removed from the
drybox. The reaction mixture was stirred at 508C for 2 h
and then cooled to room temperature. The mixture was
quenched with NH4Cl(aq.) (20 mL) and extracted with MTBE
(3”15 mL). Combined organic extracts were dried
(Na2SO4), concentrated and crude product was purified by
column chromatography on silica gel (~17 g). The condi-
tions for chromatography and data for characterization of
the products are reported as supporting information.
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