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Palladium-Catalyzed Stereospecific Oxidative Cascade Reaction of Allenes for the Construction of Pyrrole Rings: Control of Reactivity and Selectivity Man-Bo Li, Erik Svensson Grape, and Jan-E. Bäckvall ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b01041 • Publication Date (Web): 29 Apr 2019 Downloaded from http://pubs.acs.org on April 30, 2019
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ACS Catalysis
Palladium-Catalyzed Stereospecific Oxidative Cascade Reaction of Allenes for the Construction of Pyrrole Rings: Control of Reactivity and Selectivity Man-Bo Li,† Erik Svensson Grape,‡ and Jan-E. Bäckvall*,† †Department
of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden of Materials and Environmental Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden ‡Department
ABSTRACT: A palladium-catalyzed oxidative cascade reaction of α-tosylamide allenes has been developed. The reactivity of the allenes is controlled by the tosylamide group. In the presence of terminal alkynes the reaction proceeds via a pathway leading to a one-pot construction of pyrrole rings. Moreover, a solvent-controlled chemoselectivity of the cascade reaction was realized leading to a stereospecific and divergent synthesis of (Z)-tetrasubstituted olefins, 2,5-dihydropyrroles, and pyrroles. Enantioenriched (Z)-tetrasubstituted olefins and 2,5-dihydropyrroles are readily synthesized by chirality transfer using this approach. KEY WORDS: stereospecific, cascade reaction, nitrogen heterocycles, solvent-controlled selectivity, allenic amide
Efficiency and selectivity are two fundamental pillars in catalysis.1 With inspiration from nature,2 considerable efforts have been made for developing catalytic cascade reactions that combine several consecutive reactions.3 The achievement of high efficiency and selectivity in cascade reactions is a challenging goal.3 Our group has been involved in palladium-catalyzed oxidative cascade reactions of unsaturated hydrocarbons for a long time.4 More recently, we became interested in the oxidative functionalization of allenes having an additional unsaturated carbon‒carbon bond,4c-f,5-7 such as enallenes,5 allenynes,6 and bisallenes7. In these cases, the additional unsaturated carbon‒carbon bond is an indispensable assisting group.4f Replacement of the additional unsaturated carbon‒carbon bond unit by alkyl, hydrogen or aryl groups inhibits the triggering of the oxidative functionalization of allenes.4f,5c On the basis of these results, we were particularly interested in investigating the reactivity of another large category of allenes bearing an α-nucleophilic functionality (e.g. OH, NHR). We designed an oxidative cascade approach for one-pot construction of pyrrole ring (Scheme 1). We envisioned that the simultaneous coordination of the nucleophilic functionality (XH) and the allene unit of substrate 1 would trigger the allene attack4f, 5i on Pd(II) via a C‒H bond cleavage to generate Int-B as a cis-Pd(II) intermediate. In the presence of an alkyne, ligand exchange and reductive elimination would produce 3 with the nucleophilic functionality (XH) and the alkynyl group on the same side of the C=C bond. Afterward, Pd-catalyzed cycloisomerization8 of 3 would give the final pyrrole ring 5, which is a core structure of a large variety of natural and bioactive compounds.9 However, there are three challenges in this palladium-catalyzed oxidative cascade approach: 1) Control of reactivity: a central question is whether the α-nucleophilic functionality could activate Pd(II) in the Pd(II)-allene intermediate (Int-A) promoting the allene attack via a C‒H bond cleavage to form vinyl palladium complex (Int-B).4f,10 2) Control of selectivity of the cascade reaction: for example, allenes bearing an α-nucleophilic functionality are known to undergo palladium-catalyzed intramolecular cyclization to give Int-B’,11 which may compete with the
R
1
X
Construction of pyrrole rings
XH (X = O or NHR'')
R
Pd(II), oxidant
5
R' 2
R
isomerization
XH CHAL 1
R
XH
R
XH cis
Pd (II)
Pd(II)
H
R'
Int-A
Int-B
R' 3
R
XH
Pd (II) Int-C
R
cyclization
X
R'
R
H
'
4
CHAL 2 R' Pd(II)
1. Control of reactivity to proceed via allene attack R Challenges 2. Control of selectivity during each step
R X X
Int-B'
3. maintenance of Pd efficiency during overall process
3'
Scheme 1. Proposed oxidative cascade approach for one-pot construction of pyrrole rings desired cascade reaction via Int-B. 3) Maintaining high efficiency of each step: the Pd catalyst should transform each species to the next species in high yield.12 Based on the strategy in Scheme 1, we initiated our attempts to realize the cascade reaction in Scheme 1 by using allene 1fa and alkyne 2a as the substrates in the presence of Pd(OAc)2 (5 mol%) and p-benzoquinone (BQ, 1.1 equiv.) in dichloromethane (DCM) at room temperature for 12 hours. Allene 1fa was found to be very reactive under the reaction conditions. However, the exclusive product was identified to be 6 in 90% yield (Scheme 2a), which is generated from intramolecular oxypalladation (Int-A to Int-B’ in Scheme 1).11 A similar reactivity was observed by replacing the α-nucleophilic OH functionality by NHPh in allenes 1fb (Scheme 2b). To our delight, when p-toluenesulfonamide (NHTs) was used as the α-nucleophilic functionality of allene 1, allene 1f afforded the desired products 3fa and 5fa in 61% and 20% yield, respectively (Scheme 2c). These results indicate that the α-nucleophilic functional group of the allene plays an important role in controlling their reactivity. With NHTs as the α-nucleophilic functionality of allene 1, we went on to optimize the reaction conditions for the construction of pyrrole 5 (for details, see Supporting Information). Catalyst
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Pd(OAc)2 (5 mol%) BQ (1.1 equiv.)
OH
EtO2C
a)
+ Ph 1fa
+ Ph 1.5 equiv.
DCM, rt, 12 h
Pd(OAc)2 (5 mol %) BQ (1.1 equiv.)
NHTs
EtO2C c)
+ Ph 1.5 equiv. 1f
CO2Et
+ N Ph 7, 65%
2a
1fb
Ph
CO2Et
Pd(OAc)2 (5 mol %) BQ (1.1 equiv.)
NHPh
EtO2C
O 6, 90%
2a
b)
by using CH3CN as the solvent (Table 1, entry 8), while in CHCl3, 5aa was obtained in 85% yield exclusively (Table 1, entry 9). With CH3OH as the solvent, although the conversion was satisfying at 60 oC, we isolated a mixture of 4aa and 5aa (Supporting Information, Table S1, entry 13). A decrease of reaction temperature to 40 oC improved the yield of 4aa to 56% (Supporting Information, Table S1, entry 14). After testing different additives, 4aa was finally obtained in 76% yield with > 30:1 of chemoselectivity in the presence of 0.1 equiv. of Et3N as the additive18 at 40 oC (Table 1, entry 10). To summarize, we realized the solvent-controlled selectivity of the cascade reaction which allowed divergent synthesis of (Z)-tetrasubstituted olefin, 2,5-dihydropyrrole, and pyrrole.19
CO2Et
DCM, rt, 12 h
1.5 equiv.
N Ph 7', 28%
NHTs
EtO2C
+
DCM, rt, 12 h
EtO2C
NTs
Ph
Ph
2a
5fa, 20%
3fa, 61%
Scheme 2. Initial attempt screening showed that Pd(OAc)2 and Pd(TFA)2 produced the corresponding 3aa and 5aa at room temperature, while Pd(PPh3)2Cl2 and PdCl2 failed to catalyze this transformation (see Supporting Information, Table S1, entries 1-4). Solvent screening showed very interesting results: 1) We observed the generation of 4aa in protic solvent (MeOH or EtOH, Table 1, entries 4 and 5); 2) CHCl3 was the best solvent for the formation of pyrrole, and improved the yield of 5aa to 41% yield at room temperature (Table 1, entry 6); 3) By using CH3CN as the solvent, 3aa was observed as the exclusive product in 22% yield at room temperature (Table 1, entry 7).13 These results demonstrate that solvent plays an important role in controlling the selectivity of the cascade reaction,14 which could be explained by: (a) CH3CN interact with Pd(II) inhibiting the Pd-catalyzed intramolecular cyclization of 3 at room temperature; (b) The relatively acidic solvent CHCl3 favor the isomerization from 4 to 5;15 (c) Protic solvent favor the conversion from 3 to 4 (Table 1, entries 4 and 5), as a proton is needed during the process. Considering that (Z)-tetrasubstituted olefin16 and 2,5-dihydropyrrole17 are highly important structures in synthetic chemistry and amongst natural compounds, and that the synthesis of these structures are challenging to synthetic chemists, we tried to realize the divergent synthesis of (Z)-tetrasubstituted olefin 3aa, 2,5-dihydropyrrole 4aa and pyrrole 5aa. As the substrate 1a was partially recovered at room temperature, attempts were made to improve the conversion of 1a by increasing the reaction temperature. Finally, at 60 oC, 3aa was obtained as the exclusive product in 92% yield Table 1. Solvent effect of the reactiona Ph
NHTs
+
1a
Ph 1.5 equiv.
Pd(OAc)2 (5 mol %) BQ (1.1 equiv.) Additive Solvent, Temp., 12 h
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With the optimized reaction conditions in hand, we investigated the scope for the divergent synthesis of 3, 4 and 5 (Scheme 3). Aromatic (2a-f) and aliphatic (2g-n) terminal alkynes 2 worked equally well with allenes 1 to give pyrroles 5 in high yields with CHCl3 as the solvent. Functional groups such as methoxy- (5ab, 5bc, and 5bd), hydroxy- (5be, 5bj, and 5bk), nitro- (5bf, 5if), and ester- (5bl and 5bm) groups are tolerated under the standard reaction conditions. Arylalkynes with electron-withdrawing groups gave a slightly higher yield (5bf) than those with electron-donating groups (5bc, 5bd), probably due to that electron-withdrawing groups promote the palladium-catalyzed cyclization of 3 (Scheme 1). To be noted, N-tosyl-N-Boc-pro pargylamine 2h reacted with allene 1b to give 5bh as the final product, which is generated from amide elimination after the cascade reaction (see ref. 20 for details). On the other hand, by using a tertiary propargylalcohol as the alkyne 2i, the hydroxyl elimination can be controlled by temperature (5bi, 5bj). Allenic amide 1 with aryl, alkyl and other functional groups such as ester substituents in the R1 or R2 position worked equally well with terminal alkynes 2 affording pyrroles 5 in high yields (5aa, 5ca-5ha). In addition to two methyl substituents, the allenes 1 with cyclobutylidene, cycloheptylidene and cyclooctylidene substituents on the terminal position worked well with alkynes 2, leading to the corresponding pyrrole 5if, 5ja, 5je21, and 5km in moderate to high yields. Unsymmetrical Allenic amide 1l bearing methyl and phenyl groups worked with alkyne 2e, affording 5le in 82% yield.
Ph
NTs
NHTs
+
Ph
Ph
NTs +
Ph
Ph
Ph
2a
3aa
5aa
4aa
Entry
Solvent
T (oC)
Yield of 3aa (%)b
Yield of 4aa (%)b
Yield of 5aa (%)b
1
DCM
25
63
0
24
2
THF
25
60
0
10
3
acetone
25
49
0
19
4
CH3OH
25
40
36
6
5
EtOH
25
38
34
5
6
CHCl3
25
44
0
41
7
CH3CN
25
22
0
0
8
CH3CN
60
92
0
0
9
CHCl3
60
0
0
85
10c
CH3OH
40
0
76
2
aThe
reaction was carried out in the indicated solvent (1 mL) using 1a (0.2 mmol), 2a (0.3 mmol), BQ (1.1 equiv.) in the presence of Pd(OAc)2 (5 mol %). bDetermined by NMR using anisole as the internal standard. c0.1 equiv. of Et3N was added.
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ACS Catalysis R2 R1
NHTs
+
Pd(OAc)2
R3 1.5 equiv.
1
Solvent
BQ
CHCl3
5
CH3OH
4
CH3CN
3
2
NO2
OMe Teiminal alkyne 2
OMe 2a
2b
N Ts 2h
2g
2c
OH
OMe
2d
Boc
2e O
OAc OH
OH
2i
2f
OCH3
2k
2l
2m
2n
OMe NTs Solvent = CHCl3
NTs
Ph
Ph
5aa, 85% NTs
n-Bu
OMe
NTs
NTs
5be, 90%
5bj, 70% (40 oC)
NTs
5ca, 77%
NTs
Ph
5da, 88%
5ea, 81% NO2
Me
NTs
NTs
NTs
n-Bu
OMe
n-Bu
5gc, 88%
NTs
OMe
Ph
NTs
OH
Ph
5bm, 87%
Ph
5ga, 70%
O OCH3
5bl, 79%
n-Bu
NTs
Ph
Ph
Ph
NTs
NTs n-Bu
NTs
5fa, 84%
OAc
n-Bu
5bk, 84%
NTs
EtO2C
5bf, 92%
NTs OH
n-Bu
Ph NTs
n-Bu
NTs OH
NTs
OH
n-Bu
n-Bu 5bd, 72%
n-Bu
5bi, 79% (80 oC)
5bh, 88%
NO2 NTs
NTs
5bc, 75%
n-Bu
n-Bu
5bg, 80%
NTs
5ab, 86%
NTs
n-Bu
OMe
5gd, 72%
O OCH3
Ph
NTs
OH
Ph Ph
5ha, 82%
5if, 52%
5ja, 80%
NTs Solvent = CH3OH
5je, 91%
NTs
NTs
Ph
NTs
5le, 82%
NTs
4ba, 77%
4bn, 68%
4ca, 70%
NTs
Ph
n-Bu
n-Bu
4aa, 76%
5km, 71%
4da, 76%
4ea, 69% OMe
OMe
Ph
NTs
EtO2C
NTs
Me NTs
NTs
NTs
Ph
Ph
n-Bu
NTs
Ph
Ph Ph
4fa, 76%
4gd, 67% Ph
NHTs
4ha, 74% Ph
4ja, 79%
NHTs
n-Bu
Solvent = CH3CN
4kd, 74%
NHTs
NHTs
NHTs
4la, 70%
EtO2C
NHTs
OMe R 3aa, 92%
Ph n-Bu
Me NHTs
Ph
3ba, 90% (R = Ph) 3bc, 88% (R = 2-MeOC6H4) 3bd, 86% (R = 4-MeOC6H4)
3ab, 89%
Ph
NHTs
NHTs
3ca, 84%
Ph
Ph
NHTs
OMe
3gc, 87%
3da, 90%
NHTs
3fa, 82%
Ph
OH
3ha, 94%
3ja, 94%
3je, 90%
NHTs
Ph 3kn, 92%
3la, 94%
o
For the synthesis of 5: the reaction was conducted in CHCl3 (1 mL) at 60 C using 1 (0.2 mmol), 2 (0.3 mmol), and BQ (1.1 equiv.) in the presence of Pd(OAc)2 (5 mol%). For the synthesis of 4: the reaction was conducted in CH3OH (1 mL) at 40 oC using 1 (0.2 mmol), 2 (0.3 mmol), and BQ (1.1 equiv.) in the presence of Pd(OAc)2 (5 mol%) and Et3N (0.1 equiv.). For the synthesis of 3: the reaction was conducted in CH3CN (1 mL) at room temperature using 1 (0.2 mmol), 2 (0.3 mmol), and BQ (1.1 equiv.) in the presence of Pd(OAc)2 (5 mol%).
Scheme 3. Stereospecific and divergent synthesis of 3, 4, and 5 By using CH3CN or CH3OH, respectively, as solvent, (Z)-tetrasubstituted olefins 3 or 2,5-dihydropyrroles 4 were selectively obtained. Allenes 1 with various substituents in the R1, R2 and terminal positions worked equally well with aryl and alkyl terminal alkynes 2 affording 3 and 4 in high yields with excellent selectivity (Scheme 3). The stereochemistry of (Z)-tetrasubstituted
olefins 3 and 2,5-dihydropyrroles 4 were established by NOESY spectra of 3bc, 3bd, and 4ba, and single crystal structures22 of 3ja and 4ha (For details, see Supporting Information). The N-tosyl group was readily removed by the treatment of pyrrole 5 under basic conditions, giving free pyrrole 8 in high
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yield (scheme 4a). Enantioenriched allenic tosylamide (R)-1h was prepared via kinetic resolution of allenic alcohol 9 with Candida antarctica lipase B (CalB), followed by a Mitsunobu reaction.23 Under the standard reaction conditions for the divergent synthesis of 3 and 4, (R)-1h was transformed to chiral (Z)-tetrasubstituted olefin (R)-3ha or 2,5-dihydropyrrole (R)-4ha in high yield without any detectable loss of optical purity (Scheme 4b). a)
NTs
NH
OH
Ph
KOH, EtOH, 80 oC, 14 h
OH
Ph
5je
8je, 94% Me
b)
Ph
NHTs
CH3CN, 60 oC
Me
Me
Ph OH i) Enzymatic KR
Ph
NHTs
Ph (R)-3ha, 95%, 94% ee
Pd(OAc)2 (5 mol%) BQ (1.1 equiv.)
ii) Mitsunobu Reaction
Ph 1.5 equiv.
CH3OH, 40 oC Et3N (0.1 equiv.)
(R)-1h, 94% ee
9
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To confirm the mechanism for the formation of 3 via C-H bond cleavage (Int-A to Int-B, Scheme 1), the deuterium kinetic isotope effect (KIE) for the reaction of 1a → 3aa was studied.25 As shown in scheme 6a, the competition KIE experiment was carried out by using a 1:1 mixture of 1a and 1a-d6 at 60oC for 20 min. The ratio of 3aa/3aa-d5 measured at 15% conversion was 4/1. From this ratio, the competitive KIE was determined to be kH/kD = 4.4. Moreover, the parallel KIE experiments (from initial rate) provided a KIE value of 2.3 (Scheme 6b and 6c). The observed KIE in both competition and parallel experiments indicate that the allenic C‒H bond cleavage is involved in the rate-limiting step. However, the difference between KIE value in competition and parallel experiments imply that this step is not totally, but only partially, rate-limiting. Furthermore, the large competitive KIE value (kH/kD = 4.4) requires that the allenic C‒H bond cleavage is the first irreversible step.26 a)
Ph
NTs Ph
Ph
Ph
Scheme 4. Removal of N-tosyl group and the synthesis of enantioenriched 3 and 4
D 3C
To gain a deeper insight into the mechanism and the role of the NHTs group for the reactivity of the reaction, we conducted several control experiments. First, we blocked the hydrogen of the α-nucleophilic functionality of allene 1f with a methyl group to form 1fc. Interestingly, treatment of 1fc with alkyne 2a under standard conditions failed to give the desired product, and 1fc was recovered in 95% yield (Scheme 5a). At the same time, the control experiments (Scheme 2a and b) also show that the use of other weakly coordinating ligands failed to give the desired product. These results suggest that the active hydrogen of allenic amide is essential for the allene attack on the Pd(II) center (from Int-A to Int-B, Scheme 1).24 The lone pair of the nitrogen atom is basically absorbed in the resonance with the sulfonyl group. We therefore conclude that the sulfonamide undergoes anionic ligand exchange with one of the X ligands on Pd(II) rather than coordinating as a neutral ligand (this is shown in Scheme 7, Int-A). Second, we treated 3aa under the standard reaction conditions for the formation of 4aa from 1a. The result showed that 3aa was transformed to 4aa in high yield (Scheme 5b). Additionally, 4aa was transformed to 5aa in CHCl3 at 60 oC (Scheme 5b). These results confirm the pathway we proposed for the formation of 4 and 5 in Scheme 1. a) NHTs
+ Ph 1.5 equiv. 1f
Pd(OAc)2 (5 mol %) BQ (1.1 equiv.)
NHTs
EtO2C
CH3CN, 60 oC, 12 h
N Ts
1fc
+ Ph 1.5 equiv.
Pd(OAc)2 (5 mol %) BQ (1.1 equiv.) CH3CN, 60 oC, 12 h
b)
Ph
Ph
NHTs
Ph
CHCl3, 60 oC, 4 h
Ph
5aa, 97%
Ph
3aa-d5
Scheme 6. Kinetic isotope effect studies Based on the experimental results, we propose the mechanism given in Scheme 7 for the cascade reaction. Initially, simultaneous coordination of the amide group and the allene unit (Int-A) would trigger the allene attack to generate Int-B. The interaction between the NHTs and the Pd(II) center is crucial for controlling the reactivity and stereoselectivity, and triggers the allene attack involving allenic C‒H bond cleavage to give a cis-intermediate Int-B. In the presence of an alkyne, ligand exchange and reductive elimination of Int-B would produce 3. Afterward, Pd-catalyzed intramolecular cyclization of 3 (via Int-C and Int-D) would give 2,5-dihydropyrrole 4, which undergoes isomerization to afford the pyrrole 5. R2 R1
R2 NHTs
-
-X
R1
R2 -
-X
NTs
1
R1
NTs
allene attack
X
Pd
Int-A
R2
Int-B
R2 R3 isomerization
R1
NTs R1
R3
H
ligand exchange and reductive elimination
2
R3
5 R2
R2 NTs
R3
cyclization
R1
R2 NHTs
Pd(II)
Ph
Int-D 4aa
CD3
1a-d6
4
NTs
NHTs
D 2C
Ph
CH3OH, 40 C, 12 h 4aa, 81%
Ph
Ph
CD3CN, 60 oC < 12% yield
CD3
D 3C
R1 NTs
(1.5 equiv.) Ph Pd(OAc)2 (5 mol %) BQ (1.1 equiv.)
NTs
3aa
Ph
3aa kH/kD = 2.3
c)
N.R. 1ac was recovered in 95% yield
NTs
NHTs
1a
Pd
Ph
Ph
CD3CN, 60 C < 12% yield
o
Ph
(1.5 equiv.) Ph Pd(OAc)2 (5 mol %) BQ (1.1 equiv.) o
H+ Pd(OAc)2 (5 mol %) Et3N (0.1 equiv.)
Ph 3aa-d 5
3aa : 3aa-d5 = 4:1
NHTs
2a
NHTs
CD3
1a : 1a-d6 = 1:1
b) Ph
NHTs
D 2C
3fa, 82%
Me
3aa
kH/kD = 4.4
Ph
CD3 1a-d 6
PdX2 + EtO2C
Ph
+
CD3CN, 60 oC, 20 min Conv. = 15%
NHTs
Ph
2a
NHTs
(1.5 equiv.) Ph Pd(OAc)2 (5 mol %) BQ (1.1 equiv.)
1a
+
(R)-4ha, 76%, 94% ee
EtO2C
Ph
NHTs
Me
Pd (II) Int-C
Scheme 7. Proposed mechanism
Scheme 5. Control experiments
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R
BQ
Pd(II)
HQ
Pd(0)
R1
NHTs
3
R3 3
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ACS Catalysis In conclusion, a palladium-catalyzed oxidative cascade reaction of allenes for one-pot construction of pyrrole rings was developed. The tosylamide group is crucial for triggering the allene attack on Pd(II), which generates the key intermediate for the formation of the desired products. Solvent-controlled selectivity of the cascade reaction was realized for divergent synthesis of (Z)-tetrasubstituted olefins, 2,5-dihydropyrroles, and pyrroles. In addition, enantioenriched (Z)-tetrasubstituted olefin and 2,5-dihydropyrrole were readily synthesized by chirality transfer via this approach. The strategy for the divergent and stereospecific construction of (Z)-tetrasubstituted olefins, 2,5-dihydropyrroles, and pyrroles would be beneficial in synthetic and material chemistry. Further studies on the α-amide-controlled reactivity of allenes are currently underway in our laboratory.
ASSOCIATED CONTENT Supporting Information Experimental procedures and compound characterization data, including the 1H/13C NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION Corresponding Author *
[email protected] Notes The authors declare no competing financial interest.
ACKNOWLEDGMENT The Swedish Research Council (2016-03897), The Foundation Olle Engkvist Byggmästare, and the Knut and Alice Wallenberg Foundation (KAW 2016.0072) is gratefully acknowledged.
REFERENCES (1) (a) Beller, M.; Renken, A.; Santen, R. v. Catalysis: From Principles to Applications; Wiley-VCH: Weinheim, Germany, 2012. (b) Fundamentals of Organometallic Catalysis, 1st ed.; Steinborn, D, Ed.; Wiley-VCH: Weinheim, Germany, 2012. (c) Nahatthananchai, J.; Dumas, A. M.; Bode, J. W. Catalytic Selective Synthesis. Angew. Chem. Int. Ed. 2012, 51, 10954-10990. (d) Svoboda, J.; König, B. Templated Photochemistry: Toward Catalysts Enhancing the Efficiency and Selectivity of Photoreactions in Homogeneous Solutions. Chem. Rev. 2006, 106, 5413-5430. (2) (a) Wheeldon, I.; Minteer, S. D.; Banta, S.; Barton, S. C.; Atanassov, P.; Sigman, M. Substrate Channelling as an Approach to Cascade Reactions. Nat. Chem. 2016, 8, 299-309. (b) Schrittwieser, J. H.; Velikogne, S.; Hall, M.; Kroutil, W. Artificial Biocatalytic Linear Cascades for Preparation of Organic Molecules. Chem. Rev. 2018, 118, 270-348. (3) For selected book and reviews, see: (a) Metal Catalyzed Cascade Reactions, 1st ed.; Müller, T. J. J., Ed.; Springer-Verlag: Berlin Heidelberg, 2006. (b) Fogg, D. E.; dos Santos, E. N. Tandem Catalysis: a Taxonomy and Illustrative Review. Coord. Chem. Rev. 2004, 248, 2365-2379. (c) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Cascade Reactions in Total Synthesis. Angew. Chem., Int. Ed. 2006, 45, 7134-7186. (d) Grondal, C.; Jeanty, M.; Enders, D. Organocatalytic Cascade Reactions as a New Tool in Total Synthesis. Nat. Chem. 2010, 2, 167-178. (e) Volla, C. M. R.; Atodiresei, I.; Rueping, M. Catalytic C–C Bond-Forming Multi-Component Cascade or Domino Reactions: Pushing the Boundaries of Complexity in Asymmetric Organocatalysis. Chem.
Rev. 2014, 114, 2390-2431. (f) Ardkhean, R.; Caputo, D. F. J.; Morrow, S. M.; Shi, H.; Xiong, Y.; Anderson, E. A. Cascade Polycyclizations in Natural Product Synthesis. Chem. Soc. Rev. 2016, 45, 1557-1569. (4) For reviews and book, see: (a) Bäckvall, J.-E. Palladium in Some Selective Oxidation Reactions. Acc. Chem. Res. 1983, 16, 335-342. (b) Modern Oxidation methods, 2nd ed.; Bäckvall, J.-E., Ed.; Wiley-VCH: Weinheim, Germany, 2011. (c) Piera, J.; Bäckvall, J.-E. Catalytic Oxidation of Organic Substrates by Molecular Oxygen and Hydrogen Peroxide by Multistep Electron Transfer—A Biomimetic Approach. Angew. Chem. Int. Ed. 2008, 47, 3506-3523. (d) Deng, Y.; Persson, A. K. Å.; Bäckvall, J.-E. Palladium-Catalyzed Oxidative Carbocyclizations. Chem. Eur. J. 2012, 18, 11498-11523. (e) Zhang, D.; Liu, J.; Córdova, A.; Liao, W.-W. Recent Developments in Palladium-Catalyzed Oxidative Cascade Carbocyclization. ACS Catal. 2017, 7, 7051-7063. (f) Yang, B.; Qiu, Y.; Bäckvall, J.-E. Control of Selectivity in Palladium (II)-Catalyzed Oxidative Transformations of Allenes. Acc. Chem. Res. 2018, 51, 1520-1531. (5) For selected examples on enallenes, see: (a) Persson, A. K. Å.; Jiang, T.; Johnson, M.; Bäckvall, J.-E. Palladium-Catalyzed Oxidative Borylative Carbocyclization of Enallenes. Angew. Chem. Int. Ed. 2011, 50, 6155-6159. (b) Zhu, C.; Yang, B.; Bäckvall, J.-E. Highly Selective Cascade C–C Bond Formation via PalladiumCatalyzed Oxidative Carbonylation– Carbocyclization–Carbonylation–Alkynylation of Enallenes. J. Am. Chem. Soc. 2015, 137, 11868-11871. (c) Zhu, C.; Yang, B.; Jiang, T.; Bäckvall, J.-E. Olefin-Directed Palladium-Catalyzed Regio-and Stereoselective Oxidative Arylation of Allenes. Angew. Chem., Int. Ed. 2015, 54, 9066-9069. (d) Qiu, Y.; Yang, B.; Zhu, C.; Bäckvall, J.-E. Palladium-Catalyzed Oxidative Carbocyclization-Borylation of Enallenes to Cyclobutenes. Angew. Chem., Int. Ed. 2016, 55, 6520-6524. (e) Qiu, Y.; Yang, B.; Zhu, C.; Bäckvall, J.-E. Highly Efficient Cascade Reaction for Selective Formation of Spirocyclobutenes from Dienallenes via Palladium-Catalyzed Oxidative Double Carbocyclization– Carbonylation–Alkynylation. J. Am. Chem. Soc. 2016, 138, 13846-13849. (f) Qiu, Y.; Yang, B.; Jiang, T.; Zhu, C.; Bäckvall, J.-E. Palladium-Catalyzed Oxidative Cascade Carbonylative Spirolactonization of Enallenols. Angew. Chem., Int. Ed. 2017, 56, 3221-3225. (g) Li, M.-B.; Posevins, D.; Gustafson, K. P. J.; Tai, C.-W.; Shchukarev, A. Qiu, Y.; Bäckvall, J.-E. Diastereoselective Cyclobutenol Synthesis: A Heterogeneous Palladium-Catalyzed Oxidative Carbocyclization-Borylation of Enallenols. Chem. Eur. J. 2018, 24, 210-215. (h) Li, M.-B.; Inge, A. K.; Posevins, D.; Gustafson, K. P. J.; Qiu, Y.; Bäckvall, J.-E. Chemodivergent and Diastereoselective Synthesis of γ-Lactones and γ-Lactams: A Heterogeneous Palladium-Catalyzed Oxidative Tandem Process. J. Am. Chem. Soc. 2018, 140, 14604-14608. (i) Posevins, D.; Qiu, Y.; Bäckvall, J.-E. Highly Diastereoselective Palladium-Catalyzed Oxidative Carbocyclization of Enallenes Assisted by a Weakly Coordinating Hydroxyl Group. J. Am. Chem. Soc. 2018, 140, 3210-3214. (6) For selected examples on allenynes, see: (a) Deng, Y.; Bartholomeyzik, T.; Persson, A. K. Å.; Sun, J.; Bäckvall, J.-E. Palladium-Catalyzed Oxidative Arylating Carbocyclization of Allenynes. Angew. Chem., Int. Ed. 2012, 51, 2703-2707. (b) Deng, Y.; Bäckvall, J.-E. Palladium-Catalyzed Oxidative Acyloxylation/Carbocyclization of Allenynes. Angew. Chem., Int. Ed. 2013, 52, 3217-3221. (c) Bartholomeyzik, T.; Mazuela, J.; Pendrill R.; Deng, Y.; Bäckvall, J.-E. Palladium-Catalyzed Oxidative Arylating Carbocyclization of Allenynes: Control of Selectivity and Role of H2O. Angew. Chem., Int. Ed. 2014, 53, 8696-8699. (7) For selected examples on bisallenes, see: (a) Zhu, C.; Yang, B.; Qiu, Y.; Bäckvall, J.-E. Highly Selective Construction of Seven-Membered Carbocycles by Olefin-Assisted
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Palladium-Catalyzed Oxidative Carbocyclization-Alkoxycarbonylation of Bisallenes. Angew. Chem., Int. Ed. 2016, 55, 14405-14408. (b) Naidu, V. R.; Posevins, D.; Volla, M. R.; Bäckvall, J.-E. Selective Cascade Reaction of Bisallenes via Palladium-Catalyzed Aerobic Oxidative Carbocyclization-Borylation and Aldehyde Trapping. Angew. Chem., Int. Ed. 2017, 56, 1590-1594. (8) Gabriele, B.; Salerno, G.; Fazio, A. General and Regioselective Synthesis of Substituted Pyrroles by Metal-Catalyzed or Spontaneous Cycloisomerization of (Z)-(2-En-4-ynyl)amines. J. Org. Chem. 2003, 68, 7853-7861. (9) For selected book and reviews on the property and synthesis of pyrrole, see: (a) Pyrroles: The synthesis and the physical and chemical aspects of the pyrrole ring, 1st ed.; Jones, R. A., Ed.; Wiley-Interscience: New York, 1990. (b) Fukuda, T.; Ishibashi, F.; Iwao, M. Synthesis and Biological Activity of Lamellarin Alkaloids: an Overview. Heterocycles. 2011, 83, 491-529. (c) Walsh, C. T.; Garneau-Tsodikova, S.; Howard-Jones, A. R. Biological Formation of Pyrroles: Nature's Logic and Enzymatic Machinery. Nat. Prod. Rep. 2006, 23, 517-531. (d) Estévez, V.; Villacampa, M.; Menéndez, J. C. Recent Advances in the Synthesis of Pyrroles by Multicomponent Reactions. Chem. Soc. Rev. 2014, 43, 4633-4657. (e) Khaghanineiad, S.; Herayi, M. M. Paal-Knorr Reaction in the Synthesis of Heterocyclic Compounds. Adv. Heterocycl. Chem. 2014, 111, 95-146. (f) Gulevich, A. V.; Dudnik, A. S.; Chernyak, N.; Gevorgyan, V. Transition Metal-Mediated Synthesis of Monocyclic Aromatic Heterocycles. Chem. Rev. 2013, 113, 3084-3213. (10) In recent work, we found that a β-hydroxy group in the enallene promotes the allenic attack on palladium to give the vinyl palladium intermediate: see ref. 5i. (11) For selected reviews, see: Ma, S. Transition Metal-Catalyzed/Mediated Reaction of Allenes with a Nucleophilic Functionality Connected to the α-Carbon Atom. Acc. Chem. Res. 2003, 36, 701-712. (b) Ye, J.; Ma, S. Palladium-Catalyzed Cyclization Reactions of Allenes in the Presence of Unsaturated Carbon–Carbon Bonds. Acc. Chem. Res. 2014, 47, 989-1000. For recent reports, see: (c) Yang, B.; Zhu, C.; Qiu, Y.; Bäckvall, J.-E. Enzyme- and Ruthenium-Catalyzed Enantioselective Transformation of α–Allenic Alcohols into 2,3-Dihydrofurans. Angew. Chem., Int. Ed. 2016, 55, 5568-5572. (d) El-Sepelgy, O.; Brzozowska, A.; Azofra, L. M.; Jang, Y. K.; Cavallo, L.; Rueping, M. Experimental and Computational Study of an Unexpected Iron-Catalyzed Carboetherification by Cooperative Metal and Ligand Substrate Interaction and Proton Shuttling. Angew. Chem., Int. Ed. 2017, 56, 14863-14867. (e) Guđmundsson, A.; Gustafson, K. P. J. Mai, B. K.; Yang, B.; Himo, F.; Bäckvall, J.-E. Efficient Formation of 2,3-Dihydrofurans via Iron-Catalyzed Cycloisomerization of α-Allenols. ACS Catal. 2018, 8, 12-16. (12) (a) Campbell, A. N.; Stahl, S. S. Overcoming the “Oxidant Problem”: Strategies to Use O2 as the Oxidant in Organometallic C–H Oxidation Reactions Catalyzed by Pd (and Cu). Acc. Chem. Res. 2012, 45, 851-863. (b) Wang, D.; Weinstein, A. B.; White, P. B.; Stahl, S. S. Ligand-Promoted Palladium-Catalyzed Aerobic Oxidation Reactions. Chem. Rev. 2018, 118, 2636-2679. (13) None of E isomer was observed by NMR. (14) For selected review and recent example on solvent-controlled selectivity of oxidations and cascade reactions, see: (a) Peng, J.-B.; Wu, X.-F. Ligand-and Solvent-Controlled Regio- and Chemodivergent Carbonylative Reactions. Angew. Chem., Int. Ed. 2018, 57, 1152-1160. (b) Jia, J.; Yu, A.; Ma, S.; Zhang, Y.; Li, K.; Meng, X. Solvent-Controlled Switchable Domino Reactions of MBH Carbonate: Synthesis of Benzothiophene Fused α -Pyran, 2,3-Dihydrooxepine, and Oxatricyclodecene Derivatives. Org. Lett. 2017, 19, 6084-6088.
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(15) Based on the experimental results, we found that the isomerization from 4 to 5 is favored under relatively acidic conditions. For example, the conversion of 4 to 5 increased in CH3OH with the addition of AcOH (Supporting Information, Table S1, entries 14 and 15), and 4 partially transformed to 5 in a long and slow column. (16) (a) Flynn, A. B.; Ogilvie, W. W. Stereocontrolled Synthesis of Tetrasubstituted Olefins. Chem. Rev. 2007, 107, 4698-4745. (b) Negishi, E.-I.; Huang, Z.; Wang, G.; Mohan, A.; Wang, C.; Hattori, H. Recent Advances in Efficient and Selective Synthesis of Di-, Tri-, and Tetrasubstituted Alkenes via Pd-Catalyzed Alkenylation-Carbonyl Olefination Synergy. Acc. Chem. Res. 2008, 41, 1474-1485. (c) Oger, C.; Balas, L.; Durand, T.; Galano, J.-M. Are Alkyne Reductions Chemo-, Regio-, and Stereoselective Enough To Provide Pure (Z)-Olefins in Polyfunctionalized Bioactive Molecules? Chem. Rev. 2012, 113, 1313-1350. (17) (a) Nguyen, U. T. T.; Guo, Z.; Delon, C.; Wu, Y.; Deraeve, C.; Franzel, B.; Bon, R. S.; Blankenfeldt, W.; Goody, R. S.; Waldmann, H.; Wolters, D.; Alexandrov, K. Analysis of the Eukaryotic Prenylome by Isoprenoid Affinity Tagging. Nat. Chem. Biol. 2009, 5, 227-235. (b) Castellano, S.; Fiji, H. D. G.; Kinderman, S. S.; Watanabe, M.; de Leron, P.; Tamanoi, F.; Kwon, O. Small-Molecule Inhibitors of Protein Geranylgeranyltransferase Type I. J. Am. Chem. Soc. 2007, 129, 5843-5845. (c) Furstner, A. Chemistry and Biology of Roseophilin and the Prodigiosin Alkaloids: A Survey of the Last 2500 Years. Angew. Chem., Int. Ed. 2003, 42, 3582-3603. (18) The addition of Et3N might inhibit the isomerization of 4 to 5, as the transformation is favored under relatively acidic conditions (ref. 15). (19) For a previous report on the generation of pyrroles by the reaction of propargyl amine with terminal alkynes, which involves similar intermediates as in the present work, see: Trost, B. M.; Lumb, J.-P.; Azzarelli, J. M. An Atom-Economic Synthesis of Nitrogen Heterocycles from Alkynes. J. Am. Chem. Soc. 2011, 133, 740-743. (20) For the generation of 5bh, see below: NTs
via n-Bu n-Bu
NHTs
+ 1b
N Ts 1h
Boc N Ts
Boc
NTs
n-Bu Pd(OAc)2, BQ, CDCl3, 60 oC 5bh
(21) The single crystal structure of 5je (CCDC 1885460) further confirms the structures of the pyrrole ring 5 that we obtained. (22) The single crystal structures of 3ja (CCDC 1885458) and 4ha (CCDC 1885459) further confirm the structures of the (Z)-tetrasubstituted olefins 3 and 2,5-dihydropyrroles 4 that we obtained. (23) For the preparation of (R)-1h, see the Supporting Information. In the kinetic resolution of 8, (S)-8 was collected. (24) Attempts to synthesize and use the allene with a more acidic directing group, such as 4-nitrobenzenesulfonamide (NS) to further confirm our conclusion were unsuccessful due problems with its preparation. (The final deprotection of the Boc group failed in this case; see the general procedure for the preparation of starting materials, page S3 of Supporting Information). (25) For details of the kinetic isotope effect studies, see the Supporting Information. (26) Simmons, E. M.; Hartwig, J. F. On the Interpretation of Deuterium Kinetic Isotope Effect in C-H Bond Functionalization by Transition-Metal Complexes. Angew. Chem., Int. Ed. 2012, 51, 3066-3072.
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Graphic Abstract R2 R1
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