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Palladium-Catalyzed Allylic Amidation with N-Heterocycles via sp3 C-H Oxidation Sandeep R. Vemula, Dinesh Kumar, and Gregory R Cook ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b01818 • Publication Date (Web): 01 Jul 2016 Downloaded from http://pubs.acs.org on July 2, 2016
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ACS Catalysis
Palladium-Catalyzed Allylic Amidation with N-Heterocycles via sp3 C-H Oxidation Sandeep R. Vemula, Dinesh Kumar, Gregory R. Cook* Department of Chemistry and Biochemistry, North Dakota State University, Fargo, North Dakota 58108-6050, USA E-mail:
[email protected] ABSTRACT: An atom economic direct intermolecular allylic amidation of electron deficient tautomerizable Nheterocycles is reported via allylic C-H activation of terminal olefins with a PdCl2 catalyst. The reaction did not require any activators (base or Lewis acid) or external ligands and proceeded with high chemo (N-vs-O)-, regio (linear-vsbranch)-, and stereoselectivity (E-vs-Z) for a variety of N-heterocycles and terminal olefins. Mechanistic investigation and stoichiometric studies validate the sulfoxide ligand assisted allylic C-H bond cleavage to form a π-allylpalladium intermediate in the reaction pathway. Excellent selectivity was observed during intermolecular competition demonstrating the differential nucleophilicity of N-heterocycles and differential susceptibility of allyl C-H bond cleavage to form πallylpalladium complexes directly from terminal olefins. KEYWORDS: palladium catalysis, allylic amidation, sp3 C-H activation, N-heterocycles, terminal olefins. N-Heterocycles constitute an important structural class of chemical substances, particularly among the natural products, biologically active structures and medicinally relevant compounds.1 Consequently their diverse functionalization is highly significant.2 The Pd-catalyzed allylic substitution (Tsuji-Trost reaction) has been instrumental to obtain structural diversity via formation of C-C and C-X (X = N, O & S) bonds, however, it generally necessitates the pre-functionalization of allyl substrates to prepare leaving groups capable of oxidative addition with Pd(0).3 Further, performing such substitutions generates a stoichiometric amount of acidic waste, requiring additional treatment for its removal, and lowers the overall efficiency (Scheme 1). While much effort has been devoted to improve the reaction to avoid preactivation and utilize allyl alcohols directly,4 a more direct and sustainable approach is functionalization via direct activation of a C-H bond.
Allylic sp3 C−H bond functionalization has emerged as a highly valuable strategy for structural modification.5 During the past decade, Pd(II)-catalysis has enabled allylic C−H oxygenation,6 amination,7 alkylation,8 carbonylation,9 silylation,10 fluorination,11 borylation,12 and dehydrogenation.13 Although these recent advances have helped address basic synthetic problems, the direct alkenylation of notorious electron deficient Nheterocycles remains a challenge. Further, multiple product pathways in the case of tautomerizable heterocycles presents question of chemo- and regioselectivity. In this communication, we report the first direct allylic C−H amidation reaction employing tautomerizable Nheterocycles. This protocol does not require any preactivation of allyl substrates or exogenous ligands or additives, and proceeds with high chemo-, regio-, and stereoselectivity.
Traditional Tsuji-Trost Reaction R
OH
stoichiometric preactivation
R
WASTE
X
X = Cl, OAc, OCOMe, etc.
NuH cat.
R
Nu
H-X WASTE
Allylic C-H Activation
R
NuH cat.
R
Nu
Sustainable Atom Economical
H2
Scheme 1. Classical Tsuji-Trost reaction vs. allylic C-H activation
Scheme 2. Preliminary investigation using White’s amination protocol We initially examined the utility of the amination protocol reported by White7d,7e for the reaction of (4H)quinazolone 1a with allylbenzene 2a (Scheme 2). However, no allylic amidation to form 3a/3b was observed under these conditions. Inclusion of known activators such as Bronsted base (DIPEA) or Lewis acid [(salen)Cr(III)Cl] did not afford any improvement. Vari-
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ation in the reaction temperature or solvents was also ineffective (see SI). Additionally, no products of C-O allylation were observed either. Thus we carried out a systematic investigation of different Pd-catalysts, solvents, and oxidants to find optimal conditions for this challenging intermolecular allylation of 1a (see Table 1 and SI).
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with DMBQ (1.5 equiv) in DMSO (1M) at 100 °C was optimal to produce 3a in 92% isolated yield with excellent chemo- and regio- and stereoselectivity (Scheme 3). Importantly, these conditions are relatively simple and do not require additional metal Lewis acid7e or base7d additives for optimization. Further, no Wacker-type oxidative products such as 3-(1-benzyl-vinyl)-3H-quinazolin4-one and/or benzyl methyl ketone were observed.
Table 1. Investigation of Pd-catalysts, solvents, and oxidants for the allylic amidation of 1a with 2a.a* O
O NH
+ Ph
N 1a
2a
Catalyst (10 mol%) Oxidant (2 equiv), Solvent (1M), 100 °C, 24 h
N
Ph
N
Entry Catalyst
Solvent
Oxidant Yield (%)
1
DMSO
DMBQ
2
Pd(OAc)2
Scheme 3. Optimized conditions for allylic amidation of 1a
3a
b c
traces d
Pd(TFA)2
DMSO
DMBQ
13
3
PdCl2
DMSO
DMBQ
90
4
(PPh3)2PdCl2
DMSO
DMBQ
0
c
5
(PhCN)2PdCl2
DMSO
DMBQ
55
6
[PdCl(allyl)]2
DMSO
DMBQ
57
7
Pd(dppf)Cl2
DMSO
DMBQ
0
8
IPrPd(allyl) Cl
DMSO
DMBQ
13
9
White Catalyst
DMSO
DMBQ
traces
10
PdCl2
DMF
DMBQ
0
11
PdCl2
MTBE
DMBQ
0
12
PdCl2
THF
DMBQ
0
13
PdCl2
DCE
DMBQ
0
14
PdCl2
1,4-Dioxane DMBQ
0
15
PdCl2
PhMe
DMBQ
0
16
PdCl2
DMC
DMBQ
0
17
PdCl2
DME
DMBQ
0
18
PdCl2
DMSO
BQ
45
19
PdCl2
DMSO
MBQ
46
20 PdCl2
DMSO
Duroquinone 48
21
PdCl2
DMSO
Oxone
59
22
PdCl2
DMSO
MnO2
29
c
c c c c c c c c
Encouraged by initial results using allylbenzene 2a, structurally different terminal olefins were investigated to demonstrate the generality of intermolecular direct allylic amidation of quinazolinone using our protocol (Table 2). A wide scope of either commercially available or readily accessible terminal olefins smoothly underwent allylic C−H amidation reaction with 1a in high yield and excellent chemo (N-vs-O)-, regio (linear-vsbranch)-, and stereoselectivity (E-vs-Z). It is significant to note that the reaction was seemingly insensitive to the electronic feature of the aryl moiety of the olefin substrates as both electron-donating (4b and 4c) and electron-withdrawing (4d) substituted allyl benzenes reacted smoothly with high yields. Fluorinated (4e and 4f), heteroaryl (4h and 4i), napthyl (4j) and sensitive piperonyl moieties (4g) were found suitable affording high yields of desired products. Aliphatic terminal olefins (4k – 4m) reacted smoothly, however slightly lower yields were obtained. Table 2. Intermolecular allylic amidation with different terminal alkenes.a,b,c O
O
NH 1a
d
O
O OCH3
N
N
X 4a, X = Me; 88% 4b, X = OMe; 89%
N
4e, 91%
O
F
N
O F
S
N 4h, 90%
F
4g, 86% O N
N N 4i, 84%
S
N N
4k, 57%
a
N 4j, 87%
O
O
O
N
O N
O
N
F
F
4f, 75%
O
CF 3
4d, 81%
N F
N N
OCH3
4c, 87%
N N
R N:O >99% L:B >99% E:Z >99%
N 4a - 4m
O N
1a (0.2 mmol) was treated with 2a (0.3 mmol, 1.5 equiv) b c under different reaction conditions. Isolated yield. Startd ing 1a was found intact. Unreacted 1a was recovered intact. *For detail, see the ESI-Table S3-S7.
N
DMBQ (1.5 equiv), DMSO (1 M), 100 °C, 24 h
N
O
a
Although Pd(OAc)2 was completely ineffective, we were delighted to discover the use of PdCl2, (PhCN)2PdCl2, and [PdCl(allyl)]2 in the presence of 2,6dimethylbenzoquinone (DMBQ) using DMSO as solvent provided encouraging results. A survey of solvents using PdCl2 as catalyst showed that the reaction was highly sensitive to the reaction media. No transformation was observed in other tested solvents (entries 10-17, Table 1). 2,6-Dimethoxy-1,4-benzoquinone (DMBQ) was found to be the most efficient oxidant, thus providing the highest yield 85% (entries 18-22, Table 1). A full optimization study (see ESI) revealed the use of 10 mol% of PdCl2
PdCl 2 (10 mol%)
R
+
O
N N 4l, 73%
Ph
N N
4m, 51%
b1
Reactions were conducted at 0.2 mmol scale. H NMR analysis of the crude reaction mixture determined the ratio c of E/Z and L/B selectivity. GC-MS analysis of the crude reaction mixture determined the ratio of N/O.
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We next examined the scope of N-heterocycles as nucleophile in the direct amidation of allylbenzene (Table 3). Differently substituted quinazolinones14 reacted well to produce high yields with excellent chemo-, regio- and stereoselectivity. Both electron-withdrawing (5a) and electron-donating (5b) quinazolinones worked well. Further, more hindered 2-substituted substrates allylated with high efficiency (5c – 5f). We envisioned that such an amidation strategy could be extended beyond the quinazolinone nucleus to other biologically relevant heterocycles with varying nucleophilicity. As shown in Table 2, we were delighted to discover that Nheterocycles such as phthalazine (5g), pyrimidine (5h), pyrazine (5i), and pyridines (5j - 5m) all reacted well with excellent yields and high chemo-, regio- and stereoselectivities under optimized conditions. This demonstrates the versatility of our methodology to afford a range of allylated heterocycles. Thus the reaction scope, particularly for the heterocycle, is highly impressive. It is noteworthy to mention the excellent N-vs-O selectivity for the pyridinone and pyrazinone nucleophiles as high selectivity is often times very difficult to achieve due to the labile nature of oxo-hydroxy tautomeric equilibria. It is interesting to note that these heterocycles produced trace amounts of byproducts resulting from O-allylation and regioisomeric allylation (linear and branched products). However, selectivity remained very high.
quinazolinone or steric hindrance of the amide N-H16 using additives might alter the outcome of the reaction. However, when carried out in the presence of different additives such as AgOTf, DIPA, DBU, Cs2CO3, AcOH or TfOH, the reaction was completely shut down (Table 4). With DIPEA and TEA present, only the exclusive formation of 3a was observed. Of particular note, no significant effect of ligands was observed on the chemoselectivity. Selective formation of 3a (>94%, N/O) was observed in presence of phosphine ligands (PPh3, PCy3), amino acid ligand (Ac-Gly-OH), and N-heteocyclic carbene ligand N,N’-bis(2,6-diisopropylphenyl)imidazol-2yliedene (IPr) (Table 4).
4
DIPEA
25
5
TEA
26
Table 3. Intermolecular allylic amidation with different N-heterocycles. a,b,c
6
Cs2CO3
7
AcOH
0
O R2
O NH
N
2a
N 5a - 5m
MeO
N
Ph
N
N
N 5c, 89%
N 5a, 88%
5b, 86%
O
O N
Ph
N(Me) 2
O
N 5f, 83%
CF3
N
Ph
Ph
Ph
N
Ph
N
Ph
N
5i, 71% N : O = 98 : 1 L : B = 96 : 4 E : Z = >99
a
5j, 71% N : O = 93 : 7 L : B = 97 : 3 E : Z = >99
Br 5k, 70%
N : O = 94 : 6 L : B = 95 : 5 E : Z = >99
CH3 5l, 72%
N : O = 91 : 9 L : B = >99 E : Z = >99
AgOTf
0
f
N/A
N/A
f
2
DIPA
0
N/A
N/A
3
DBU
0
f
N/A
N/A
g
100: 0: 0
15
100: 0: 0
15
0
f
N/A
N/A
f
N/A
N/A
N/A
N/A
100: 0: 0
16
g
f
8
TFA
0
9
PPh3
25
g
98: 2: 0
62
g
100: 0: 0
N/A
f
12
bpy
0
N/A
N/A
13
rac-BINAP
0
f
N/A
N/A
14
Ac-Gly-OH
85
96: 4: 0
68
15
IPr
54
95: 5: 0
41
e
a
O N
3a/Yield (%)
1
7
N
c,d
3a: 3b: 3c
Conv
77
Ph
3c
Additive
PCy3
N
b
+ 3a + 3b
N
Entry
Bphen
5h, 74% N : O = 92 : 8 L : B = 95 : 5 E : Z = >99
O N
2a
N
DMBQ (1.5 equiv), DMSO (1M), 100 °C, 24 h
11
Ph
5g, 76% N : O = >99 L : B = >99 E : Z = >99
Ph
Ph
O
PdCl 2 (10 mol%) Additive (20 mol%)
10
O N N
O
O Ph
Ph
NH 1a N +
O
N Ph 5d, 82%
CH 3
O
N : O = >99 L : B = >99 E : Z = >99
Ph
O N
N 5e, 81%
Ph R1
O
Ph
N
N
N
DMBQ (1.5 equiv), DMSO (1 M), 100 °C, 24 h
O
O Cl
R2
PdCl 2 (10 mol%)
Ph
+
R1
Table 4. Investigation of additives effect on the PdCl2catalylyzed the allylic C-O bond formation.a
CF3 5m, 74%
N : O = 97 : 3 L : B = 92 : 8 E : Z = >99
b1
Reactions were conducted at 0.2 mmol scales. H NMR analysis of the crude reaction mixture determined the ratio c of E/Z and L/B selectivity. GC-MS analysis of the crude reaction mixture determined the ratio N/O selectivity.
The appearance of trace amounts of O-allylated products with other heterocycles prompted us to investigate their formation from quinazolinone 1a in hopes of optimizing an alternative reaction pathway. We envisioned alteration of the tautomeric equilibrium15 of the
1a (0.2 mmol) was treated with 2a (0.3 mmol, 1.5 equiv) under optimized conditions in presence of different addib 1 tives (20 mol%). Based on H NMR of the crude reaction c1 mixture with respect to 1a. H NMR analysis of the crude reaction mixture determined the ratio of E/Z and L/B selecd tivity. GC-MS analysis of the crude reaction mixture dee f termined the ratio N/O selectivity. Isolated yield. Starting g 1a was found intact. Unreacted 1a was recovered intact.
The observed high chemoselectivity for N-allyaltion with 1a and other N-heterocycles could result from an initial O-allylation followed by an allylic rearrangement (Scheme 4). This could proceed via a thermal17 or Lewis acid catalyzed [3,3]- sigmatropic rearrangement18 or a Pd(II)-catalyzed allylic migration.19 To investigate this further, the proposed O-allylated intermediate 6 was independently prepared20 and subjected to various conditions. A concerted (thermal or Lewis acid-promoted) [3,3]-sigmatropic rearrangement was ruled out as the starting material 6 remained intact
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upon heating in DMSO at 100 °C for 24 h with or without a Lewis acid catalyst present. In contrast, when treated with a Pd(II) catalyst under conditions optimized for the allylic amidation reaction, 6 was exclusively converted to the rearranged branched product 7b with no formation of linear 7a. As only the branched regioisomer was obtained, reionization of the allylic species to form the bis-allyl complex A (Scheme 4, Path A) does not appear to be operating. This rearrangement most likely occurred via Path B by a stepwise aminopalladation to form B followed by elimination to produce 7b. While these observations demonstrate that a Pd(II)-catalyzed allylic rearrangement from 6 is possible, it is unlikely to be an intermediate in the C-H activation/allylic amidation process since the linear Nallylated product 3a was formed exclusively in the latter process.
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however in only trace amount (
