Beyond the limits: Palladium-N-heterocyclic carbene-based catalytic system enables highly efficient [4+2] benzannulation reactions

Article abstract of DOI:10.1002/adsc.201100983

A highly efficient catalytic system for the palladium-catalyzed [4+2] benzannulation reaction of enynes and enynophiles has been developed. The use of an N-heterocyclic carbene-based palladium precursor allowed us to achieve turnover numbers up to 1800. T

Full text of DOI:10.1002/adsc.201100983

UPDATES
DOI: 10.1002/adsc.201100983
Beyond the Limits: Palladium-N-Heterocyclic Carbene-Based
Catalytic System Enables Highly Efficient [4+2]Benzannulation
Reactions
Olga V. Zatolochnaya,a Alexey V. Galenko,a and Vladimir Gevorgyana,*
a
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061, USA
Fax : (+1)-312-355-0836; e-mail: vlad@uic.edu
Received: December 27, 2011; Published online: April 13, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100983.
Abstract: A highly efficient catalytic system for the
palladium-catalyzed [4+2] benzannulation reaction
of enynes and enynophiles has been developed. The
use of an N-heterocyclic carbene-based palladium
precursor allowed us to achieve turnover numbers
up to 1800. The new catalytic system has enabled
an expansion of the scope of the [4+2]homo-ben-
zannulation reaction.
this chemistry, thus expanding the scope of the homo-
benzannulation procedure (Scheme 1, B).
We were interested in improving efficacy of the pal-
ladium-catalyzed [4+2]benzannulation reaction,[7]
a catalytic version of the Danheiser benzannulation.[8]
This cycloaddition reaction of conjugated enynes with
enynophiles opens a straightforward access to densely
substituted aromatic compounds. Since the first re-
ports on the homo-benzannulation of enynes[9] with
the formation of styrenes and cross-benzannulation
with diynes[10] toward arylalkynes, the scope of this
useful transformation has been systematically investi-
gated.[11] Thus, phenols,[11a] aryl ethers,[11b] anilines,[11c]
coumaranones,[11a] benzylphosphine oxides,[11d] aryl-
stannanes,[11e] cyclophane-type compounds,[11f–i] 2,6-di-
arylstyrenes,[11j] as well as precursors for 4-arylphenan-
Keywords: benzannulation; cycloaddition; N-het-
ACHTUNGTRENNUNG
In the era of sustainable chemistry, the development threnes,[11k,l] have been synthesized via this methodol-
of highly active catalytic systems for atom- and step- ogy. Combination of this process with alkyne dimeri-
economical processes is on high demand.[1] Transition zation[12a] or Sonogashira cross-coupling[12b] protocols
metal-catalyzed cycloaddition reactions are an exam- led to the development of multicomponent cascades.
ple of transformations of this kind, since the construc- However, the reaction often requires high catalyst
tion of two or more bonds occurs in a single step loading (5 mol% or more) and long reaction times,
without formation of by-products.[2] One of the ways which significantly limits its synthetic applicability.
to improve the activity of the catalytic system in tran- Although a substantial improvement of catalytic ac-
sition metal catalysis is the stabilization of the reac- tivity has been achieved by introduction of a Lewis
tive metal complex, which allows for high turnover
numbers (TONs) of the catalyst. Thus, a number of li-
gands has been designed, employment of which re-
sulted in efficient protocols for Rh-[3] and Cu-cata-
lyzed[4] cycloaddition reactions. Despite the immense
progress made in the development of high TON Pd-
catalyzed cross-coupling reactions,[5] to the best of our
knowledge, the first example of a cycloaddition reac-
tion catalyzed by palladium complexes with high
TON is yet to described.[6] Herein, we report a highly
active catalytic system for the Pd-catalyzed [4+
2]benzannulation reaction, which not only enabled
a dramatic improvement of the TON up to 1800
(Scheme 1, A), but also overcame the limitations of Scheme 1. The Pd-catalyzed [4+2]benzannulation reaction.
Adv. Synth. Catal. 2012, 354, 1149 – 1155
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Olga V. Zatolochnaya et al.
Table 1. Optimization of the reaction conditions for the Pd-catalyzed [4+2]benzannulation reaction.[a]
UPDATES
Entry
Pd, n [mol%]
Ligand
Base
T [8C], t [h]
C [M]
Yield [%][b]
1
2
3
4
5
6
7
8
Pd2dba3, 1.5
Pd2dba3, 1.5
Pd2dba3, 1.5
Pd2dba3, 1.5
Pd2dba3, 1.5
Pd2dba3, 1.5
IPrPdPPh3, 1.5
IPrPdAllCl, 1.5
IPrPdAllCl, 0.5
IPrPdAllCl, 0.1
IPrPdAllCl, 1.0
IPrPdAllCl, 1.0
IPrPdAllCl, 1.0
IPrPdAllCl, 1.0
IPrPdAllCl, 1.0
IPrPdAllCl, 0.1
IPrPdAllCl, 0.05
PPh3
A1
DPPF
C1
C1, PPh3
C2
–
–
–
80, 80
80, 80
80, 80
80 120
80, 66
120, 20
80, 40
80, 40
80, 100
80, 100
100, 25
100, 25
100, 8
120, 15
120, 15
120, 15
120, 40
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.5
10
74
69
0[c]
0[c]
82
Cs2CO3
Cs2CO3
Cs2CO3
–
58
67
77
–
PPh3
PPh3
PPh3
TFP
A1
A1
A1
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
9
75
10
11
12
13
14
15
16
17
21[d]
80
83
85
39[d]
74
A1
TFP[e]
TFP
86
85
20
[a]
Reaction conditions: 1a (0.1 mmol), 2a (0.11 mmol), Pd (n mol%), ligand (5n mol%), base (10n mol%) in dry toluene.
GC/MS yield at 100% conversion of enyne.
No reaction was observed.
Conversion was not complete.
[b]
[c]
[d]
[e]
TFP=trisACHTUNGTRENNUNG(2-furyl)phosphine.
acid or a Brønsted base[13] to the reaction media, the erocyclic carbene (NHC) ligands C[17] (Figure 1) were
turnover number of the palladium catalyst remains examined. It was found that the employment of 2-
limited to 20.
diphenylphosphino-2’-(N,N-dimethylamino)biphenyl
To this end, the cross-benzannulation reaction of (PhDavePhos, A1) did not provide any improvement
enyne 1a and diyne 2a toward arylalkyne 3a was compared to the standard reaction conditions
tested (Table 1).[14] We turned our attention to those (Table 1, entries 1 and 2). Disappointingly, no reaction
ligands which show superior performance in high was observed in the presence of 1,1’-bis(diphenyl-
TON Pd-catalyzed cross-coupling reactions and relat- phosphino)ferrocene (DPPF) (entry 3). Several com-
ed processes. Thus, biphenylphosphine ligands A,[15] mercially available bidentate ligands were also tested
multidentate ferrocene-based ligands B,[16] and N-het- to mimic the highly active multidentate analogs B.
However, ferrocene-based phosphines, as well as
other bidentate ligands, were ineffective in this reac-
tion.[14] Likewise, employment of 1,3-bis(2,6-diisopro-
pylphenyl)imidazolium chloride (IPr·HCl, C1) as an
NHC-ligand precursor did not promote the reaction
(entry 4). On the other hand, a combination of NHC
and phosphine ligands resulted in an improvement of
the reaction yield (entry 5).[18] Utilization of mixed
ligand C2[19] or defined IPrPdPPh3 catalyst[20] was not
beneficial (entries 6 and 7). Gratifyingly, employment
Figure 1. Typical ligands for high TON catalytic systems for
the Pd-catalyzed transformations.
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Beyond the Limits: Palladium-N-Heterocyclic Carbene-Based Catalytic System
Table 2. The scope of enynes in the Pd-catalyzed [4+2]benzannulation reaction.[a]
Entry
1
Enyne
Product
Yield [%][b]
83
TON[c]
1a
1b
3aa
3ba
1660 (20)[13]
2
3
86
71
1720
1420
1c
3ca
4
1d
1e
1f
1g
1h
1i
3da
3ea
3fa
3ga
3ha
3ia
85
87
84
53
75
41
77
69
90
1700
5
1740 (17)[12a]
1680
6
7
1060
8
1480 (15)[13]
820 (15)[13]
1540
9
10
11
1j
3ja
3ka
3la
1k
1l
1380 (11)[12a]
1800
12
[a]
Reaction conditions: 1 (1 equiv.), 2a (1.1 equiv.), IPrPdAllCl (0.05 mol%), TFP (0.25 mol%), CsOPiv (0.5 mol%) in dry
toluene (20M).
Isolated yield.
[b]
[c]
TON is equal to [(product mol)ꢁ(catalyst mol)À1], previously reported TON values are given in parentheses.
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Olga V. Zatolochnaya et al.
UPDATES
Table 3. The scope of diynes in the Pd-catalyzed [4+2] benzannulation reaction.[a]
Entry
Diyne
Product
Yield [%][b]
TON[c]
1
2
3
41
820
620
168
2b
2c
3db
3dc
62[d]
84[e]
4
5
77[e]
154
196
2d
3dd
88[e]
6
7
2e
2f
2b
3de
3df
3ab
59
1180
32
620
8
55[d,f]
550 (17)[10c]
[a]
Reaction conditions: 1d (1 equiv.), 2 (1.1 equiv.), IPrPdAllCl (0.05 mol%), TFP (0.25 mol%), CsOPiv (0.5 mol%) in dry
toluene (20M).
[b]
[c]
[d]
[e]
[f]
Isolated yield.
TON is equal to [(product mol)ꢁ(catalyst mol)À1], the previously reported TON value is given in parentheses.
IPrPdAllCl (0.1 mol%), TFP (0.5 mol%), CsOPiv (1.0 mol%) in dry toluene (10M).
IPrPdAllCl (0.5 mol%), TFP (2.5 mol%), CsOPiv (2.5 mol%) in dry toluene (2M).
(3-Methylbut-3-en-1-ynyl)benzene 1a was used.
of the Pd NHC-based pre-catalyst IPrPdAllCl result- yield (entry 15). Finally, in the presence of trisACHTUNGTRENNUNG(2-fur-
ed in a shortened reaction time (entry 8). It also al- yl)phosphine (TFP) ligand under nearly neat condi-
lowed us to reduce the amount of catalyst to tions, a TON higher than 1600 has been achieved
0.5 mol% (entry 9). Further decreasing the catalyst (Table 1, entry 17)!
loading led to the termination of the reaction at
Next, the enyne generality in this highly efficient
about 20% conversion (entry 10). Among phosphine [4+2]cross-benzannulation reaction, catalyzed by
co-ligands, electron-rich phosphines were the most ef- IPrPdAllCl/TFP/CsOPiv system, was investigated
ficient (entries 11 and 12). Cesium carboxylates were (Table 2). It was found that arylenynes possessing
found to be superior compared to other inorganic electron-poor aromatic substituents were slightly
bases tested. Thus, the reaction was completed within more efficient compared to their electron-rich coun-
8 h in 85% yield in the presence of CsOPiv terparts (entries 1–3). Enynes bearing 1,3-dialkyl sub-
(entry 13), although a high TON was still illusionary stitution smoothly underwent benzannulation reaction
(entry 14). Expectedly, an increase of the concentra- regardless of the substituent size at the C-3 position
tion gave a reasonable improvement of the reaction (entries 4 and 5). The least reactive 1,4-disubstituted
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Beyond the Limits: Palladium-N-Heterocyclic Carbene-Based Catalytic System
Table 4. The scope in the Pd-catalyzed [4+2]homo-benzan-
nulation of 1,3-disubstituted enynes.[a]
substrate 1g gave the product in diminished yield
(entry 7), however 1,3,4-trisubstituted enyne 1h react-
ed well (entry 8). Enynes bearing a masked hydroxy
group provided access to phenol 3ia, benzyl 3ja, and
homobenzyl alcohol 3ka derivatives (entries 9–11). A
substrate possessing a tertiary amine group reacted
smoothly to give the corresponding ortho-alkynylben-
zylamine 3la (entry 12).
The scope of diynes is presented in Table 3. Due to
low solubility of 1,4-diphenylbutadiyne under the re-
action conditions, the benzannulation proceeded to
about 50% conversion, thus providing a poor yield of
the product (entry 1). However, decreasing the con-
centration allowed us to obtain the corresponding
biarylalkyne 3db in 84% yield, although a higher cata-
lyst loading was required under more dilute condi-
tions (entries 2 and 3). Analogously to the reactivity
trend observed for enynes, electron-deficient diaryl-
Entry Enyne
Product
Yield
[%][b]
1
2
3
4
5
6
1a
1b
1c
1d
1j
4a 80
4b 89
4c 47
4d 77
4j 73
4l 76
ACHTUNGTRENNUNGdiyne 2d gave a better yield of the corresponding
product compared to that for electron-rich compound
2c (entries 4 and 5). The diyne possessing a protected
alcohol moiety underwent benzannulation in slightly
diminished yield (entry 6). Unlike the corresponding
enyne 1l, diyne 2f bearing an amine functionality
gave an unsatisfactory yield due to its decomposition
(entry 7).
Next, we turned our attention to the Pd-catalyzed
[4+2]homo-benzannulation reaction. Although the
[4+2]homo-benzannulation of 1- or 3-monosubstitut-
ed enynes is well elaborated[9] (Scheme 1, B), the
homo-benzannulation of disubstituted enynes was
limited to electron-deficient substrates only.[9b,12b] No-
tably, during the initial optimization of the cross-ben-
zannulation reaction the formation of a trace amount
of the enyne dimer was observed. We found this
result quite surprising, as 1,3-disubstituted electron-
neutral enynes did not undergo homo-dimerization
reaction before.[9] We decided to investigate the po-
tential homo-benzannulation reaction of disubstituted
enyne 1a. It was found that in the presence of
1.5 mol% of IPrPdAllCl, 3 mol% of tris(p-methoxy-
phenyl)phosphine and 3 mol% of Cs2CO3 in toluene
(1M) enyne 1a underwent homo-benzannulation pro-
viding the corresponding styrene derivative 4a in 65%
unoptimized yield. Brief optimization of the reaction
1l
[a]
[b]
Reaction conditions: 1 (1 equiv.), IPrPdAllCl (0.5 mol%),
RuPhos (2.5 mol%), CsOPiv (2.5 mol%) in dry toluene
(5M).
Isolated yield.
conditions revealed that the catalyst loading could be from the corresponding alkoxymethyl- and aminome-
reduced to 0.5 mol% with enhanced yield by employ- thylenynes (entries 5 and 6).
ment of 2-dicyclohexylphosphino-2’,6’-diisopropoxy-
In summary, a highly efficient catalytic system for
1,1’-biphenyl (RuPhos) ligand and CsOPiv (Table 4, the palladium-catalyzed [4+2]benzannulation reac-
entry 1).[14] The scope of this transformation was also tion of enynes with enynophiles has been developed.
examined. Expectedly, electron-deficient substrate 1b The newly found conditions enabled the synthesis of
provided the desired product in higher yield (entry 2), a variety of densely substituted arylacetylenes with
whereas the reactivity of electron-rich enyne 1c was high turnover numbers of the palladium catalyst.
lower (entry 3). Bis-1,3-dialkyl substituted enyne 1d Moreover, the new catalytic system allowed us to
reacted efficiently to afford styrene 4d (entry 4). Like- expand the scope of this transformation, as previously
wise, styrenes 4j and 4l with alkoxy and alkylamine unreactive 1,3-disubstituted enynes underwent
moieties were effectively synthesized in good yields smooth homo-benzannulation to afford multisubsti-
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Olga V. Zatolochnaya et al.
UPDATES
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tuted styrenes. The development of the pre- and post-
benzannulation cascades employing this highly active
catalytic system is underway in our laboratory.
Experimental Section
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General Procedure for the Palladium-Catalyzed
[4+2]Cross-Benzannulation Reaction
Enyne
1 (1.0 mmol, 1 equiv.) and diyne 2 (1.1 mmol,
1.1 equiv.) were placed in an oven-dried 0.5-mL V-vial,
equipped with a stirring bar. CsOPiv (1.2 mg, 0.005 mmol,
0.5 mol%) was added under an N2 atmosphere. Stock solu-
tion (50 mL) of IPrPdAllCl (0.0005 mmol, 0.05 mol%) and
(2-furyl)3P (0.0025 mmol, 0.25 mol%) in toluene were added
via a microsyringe under an N2 atmosphere and the reaction
vessel was capped with a syringe valve. The reaction mixture
was stirred at 1208C for 40–120 h. The reaction was moni-
tored by GC/MS analysis. Upon completion the resulting
mixture was cooled down to room temperature, diluted with
dichloromethane, and filtered through a celite plug. The fil-
trate was concentrated under a reduced pressure. The crude
product was purified by column chromatography on silica
gel to afford 3.
General Procedure for the Palladium-Catalyzed
[4+2]Homo-Benzannulation Reaction of Enynes
Enyne 1 (0.5 mmol, 1 equiv.) was placed to an oven-dried
0.5-mL V-vial, equipped with a stirring bar. IPrPdAllCl
(1.4 mg, 0.0025 mmol, 0.5 mol%), RuPhos (5.8 mg,
0.0125 mmol, 2.5 mol%), CsOPiv (2.4 mg, 0.0125 mmol,
2.5 mol%) and toluene (100 mL) were added under an N2 at-
mosphere and the reaction vessel was capped with a syringe
valve. The reaction mixture was stirred at 1208C for 15–
48 h. The reaction was monitored by GC/MS analysis. Upon
completion the resulting mixture was cooled down to room
temperature, diluted with dichloromethane and filtered
through a celite plug. The filtrate was concentrated under
reduced pressure. The crude product was purified by
column chromatography on silica gel to afford styrene 4.
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Acknowledgements
The support of the National Science Foundation (CHE-
1112055) is gratefully acknowledged.
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[14] See the Supporting Information for details.
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