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Formation of Highly Substituted Indenes through Acid Promoted Cyclodehydration with Nucleophile Incorporation Annaliese Selina Dillon, Daniel Jarrah Kerr, and Bernard L. Flynn J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 23 Jan 2019 Downloaded from http://pubs.acs.org on January 23, 2019
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The Journal of Organic Chemistry
Formation of Highly Substituted Indenes through Acid Promoted Cyclodehydration with Nucleophile Incorporation. Annaliese S. Dillon, Daniel J. Kerr and Bernard L. Flynn* Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052 Victoria Australia O
O
H
R
O
R
strong nucleophile (Nu)
O
H
R' Nu
R''
- H 2O (cyclodehydration) R
O
R'
R' R''
R'' R Knoevenagel condensation
-H2O (cyclodehydration)
O
11 examples R'
R''
Nu
weak nucleophile (Nu)
ABSTRACT: Readily accessible 3-aryl-2-carboxypropenones (by Knoevenagel condensation) undergo acid promoted cyclodehydration with nucleophile incorporation to form highly substituted indenes. For stronger nucleophiles, nucleophile incorporation precedes cyclodehydration in a nucleophilic-addition-cyclodehydration (NAC) process. For weaker nucleophiles, cyclodehydration precedes nucleophile incorporation in a cyclodehydrative-nucleophilic-trapping (CNT) sequence involving a reactive allyl cation intermediate. The substrate scope and preferred cyclization pathway (NAC or CNT) has been studied with respect to 3-aryl-2-carboxypropenone and the nature of the nucleophile. Also, for 1,3-diaryl-2-carboxypropenones, that can also undergo Nazarov cyclization, delineation between competing Nazarov and CNT pathways is controlled by the nature of the acid catalyst.
INTRODUCTION The indane ring system has proven to be a useful scaffold in the development of novel drug leads, eg 1-3, and is present in many natural products, such as the resveratrol dimer (-)quadrangularin A 4 (Fig 1).1 Many of these (and other) indanes have been prepared through Nazarov cyclization of 1-aryl-2carboxypropenones 5 (R1 = aryl) → 6 (Scheme 1).1,2 Herein, we report an alternative cyclization pathway for 3-aryl-2carboxypropenones 5 (R3 = aryl) that incorporates a nucleophile (Nu) to give indenes 7Nu. This process emulates the nucleophilic-trapping achievable in the Nazarov cyclization of divinyl ketones 5 (R1 = vinyl) to give highly substituted cyclopentanones 6Nu.3 This Nu-trapping is not possible in the Nazarov cyclization of 5 (R1 = aryl) to give indanones, where re-aromatization out-competes Nu-trapping. In this sense, our new approach to indenes nicely complements Nazarov reaction as an indene forming reaction that incorporates a Nu. Nuincorporation can occur either as a nucleophilic-additioncyclodehydration (NAC) or cyclodehydrative-nucleophilictrapping (CNT) process (see below).4 In the course of these studies we have also identified reaction conditions that enable 1,3-diaryl-2-carboxypropenones 5 (R1&3 = Ar) to give either 6 or 7Nu depending on the nature of the catalyst.
Figure 1. Bioactive and naturally occurring indanes OMe HO
O
nPrO
O OH
MeO
OMe
O
MeO
OMe MeO
HO O
O
MeO OMe
NH
N
OH
O
OH OH
Ph
3 Nuclear factor-B inhibitor
2 Tubulin polymerisation inhibitor
Scheme 1. Nazarov cyclization and incorporating cyclodehydration reactions. NAC or CNT (this work): R1 O R
3
nucleophile-
Nazarov cyclization (previous studies): O Acid R3 = aryl + Nu R1
Nu 7Nu NAC = nucleophilic-addition-cyclodehydration CNT = cyclodehydrative-nucleophilic-trapping Nu = added nucleophile
Acid R1 = aryl
O
R
O R2
R3
6
R3 5
O
1
R2
R2
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OH 4 (-)-quadrangularin A
OMe
O 1 Endothelin receptor antagonist
OH
OH
S
O Acid R1 = vinyl + Nu
O
Nu R1
R2 6Nu
R
3
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RESULTS AND DISCUSSION
Page 2 of 13
MeSO3H and tetrabutylammonium chloride (TBAC) (entry 6). However, in this case chromatography on silica gel was employed in the purification step, which led to partial doublebond isomerism to give a mixture of 7aCl and 7aCl'. Further exposure of this mixture to silica gel (stirred dichloromethane solution of 7aCl/7aCl' with suspended silica gel) led to complete conversion to 7aCl' 62% (from 5a) (entry 6).9 Based on our proposed CNT mechanism (Scheme 2, Path A) the observed decomposition of 5a in the presence of FeCl3 and MeSO3H at room temperature can be explained through the instability of reactive intermediate 10 in the absence of a suitable nucleophile to trap it. By contrast, 5a is quite stable in the presence of AlCl3 at elevated temperature (80 °C, 192 h), undergoing slow conversion to the Nazarov product 6a. This Nazarov reaction exhibits a remarkable rate enhancement with TiCl4 and is complete within 1 h at 0 °C. These very different reactivity and chemoselectivity properties for the different Lewis and Brønsted acids would appear to reside in their relative capacity to form and cyclize through Complex A or B (eq 5). Where the Nazarov product 6a may either form through an intramolecular SEAr reaction (B) or a more orthodox 4πelectrocyclization mechanism (not shown). The nature of the properties of each acid involved in promoting either cyclization are yet to be discerned and require further study.
Our discovery of the CNT reaction emerged from attempts to convert 1,3-biaryl-2-carboxypropenone 5a to indanone 6a by Nazarov cyclization (Table 1), as part of a broader investigation into the synthesis of bioactive indanes.4 Substrate 5a was formed from reductive-coupling of 3-methoxybenzoyl chloride to arylpropiolamide 86 (eq 1). To our surprise treatment of 5a with MeSO3H or FeCl3 in dichloromethane (DCM) did not lead to the Nazarov cyclization product 6a, but rather slow conversion to a complex mixture at rt over 24 h (Table 1, entries 1 and 2). This contrasted with previously reported Nazarov cyclizations on very similar substrates, 5b and 5c, using Brønsted and Lewis acids to give 6b and 6c, respectively (eq 21a and 37,8). When AlCl3 was employed as a Lewis acid in 1,2dichloroethane (DCE), 5a did not decompose but underwent slow conversion to the Nazarov product 6a upon heating to 80 °C (30% conversion after 8 days) (entry 3). The use of TiCl4 resulted in quantitative conversion of 5a to 6a within 1 h at 0 °C (entry 4). While the use of either MeSO3H or FeCl3 individually promoted the decomposition of 5a, when the two were combined the formation of a different indene product 7aCl (55%) was achieved (entry 5). Indene 7aCl is rationalized as a CNT product (Scheme 2, Path A, Nu = Cl), arising from reaction of 5a with HCl produced in situ from the reaction of FeCl3 with MeSO3H. The same product was formed using Table 1. Nazarov and NAC/CNT reactions of 5a O
O
MeO
O
MeO NMe2 OMe
OMe
O
Conditions
NMe2
OMe
OMe
OMe
OMe
MeO
O
MeO
MeO
NMe2
MeO
Cl
MeO
OMe 6a (Nazarov product)
5a
OMe
OMe
7aCl (CNT product)
O NMe2 Cl 7aCl' (CNT, double-bond migration product)
Entry
Acid
Solvent
Time (h)
Temp.
1
MeSO3H 10 equiv
DCM
18
rt
decomposition
2
FeCl3 1.3 equiv
DCM
18
rt
decomposition
3
AlCl3 1.3 equiv
DCE
192
80
6a 30%a + 5a 70%a
4
TiCl4 1.3 equiv
DCM
1
0
6a 100%
5
FeCl3 1.3 equiv, MeSO3H 10 equiv
DCM
18
rt
7aCl (recryst) 55%
6
MeSO3H 10 equiv, TBAC 1.3 equiv
DCM
18
rt
7aCl' (chromat) 62%
a
°C
Isolated yield not determined (based on 1H NMR of crude reaction mixture)
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Product
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The Journal of Organic Chemistry Me2N
O Pd(PPh3)4 5 mol%, Bu3SnH CH2Cl2, CuCl 10 mol% 3-methoxybenzoyl chloride
MeO
5a 97% (eq 1)
in the Knoevenagel condensation reaction with aldehydes has not previously been described.10,11 Scheme 3. Knoevenagel condensation to form benzylidene1,3-dicarbonyls.
OMe OMe 8
Knoevenagel condensation: O
Ph O
nPrO
Ph O
N
nPrO
O
O
R1
O
O
+ R2 Ar
Piperidine, AcOH DCE
O O
O
O NMe2
O
ACl3 CH2Cl2, rt
OMe OMe
R3
O
O
O
OMe
(eq 3)
(ref. 7) OMe
OMe
MeO
R2
O
Ph
N
R1
MeO
5c8
R2
R3
5d R1 = R2 = R3 = OMe (79%) 5e R1 = R3 = OMe, R2 = H (93%) 5f R1 = R2 = OMe, R3 =H (59%) 5g R1 = R3 = H, R2 = OMe (60%) 5h R1 = OMe, R2 = R3 = H (78%) 5i R1 = R2 = R3 = H (85%)
OEt
MeO
R2
R2
5k R1 = R2 = R3 = OMe (88%) 5l R1 = R3 = OMe, R2 = H (73%)
OMe 6c 78%
O
Ph
O
R1
O
O
Ar
O
6b 85%
5b
O
5
-ketoesters:
O
Ph
O
O
O
-ketoamides:
(eq 2)
(ref. 1a)
O
O
O R1
N
MeSO3H toluene, rt
O
O
OMe
5m R2 = OMe (71%) 5n R2 = H (78%)
1,3-diketones: O
O
O Ph
O
O Ph
Ph
O Ph
OMe OMe
Scheme 2. Proposed mechanism of indene formation. OMe
O
H
5o (47%)
O
R1
Path A cyclization (slow)
R2
R2 9
5 Path B strong NuH (fast) O R
H
- H 2O R1
O
1
R
O R2
2
R3'
Nu
R3'
10
11 weak NuH (fast)
cyclization (fast)
H 2O R 1 O
R1
12
O 3(MeO)Ph
R2
R3'
Nu
M
O
- H 2O
R2
R3'
7Nu
O
O MeO
M
Nu
O
MeO
NMe2 OMe
MeO
OMe
NMe2
(eq 5) OMe Complex A CNT-pathway M = FeCl3, H+, BF3.THF
MeO 5q (77%)
H 2O R 1 O R3'
R3'
MeO 5p (67%)
OMe OMe
OMe Complex B Nazarov-type-pathway M = TiCl4, AlCl3
To further explore the scope of these cyclodehydration processes a series of other α-benzilidine-β-1,3-dicarbonyls 5 were formed through Knoevenagel condensation (Scheme 3). Notably, β-ketoamides (R2 = NR2) gave exclusively Z-isomers and β-ketoesters exclusively E-isomers (only symmetrical ketones were prepared). Interestingly, such complete stereodivergence between equivalent β-ketoesters and amides
Substrates 5 were cyclized using either a Brønsted or Lewis acid (MeSO3H and BF3.THF, respectively) in the presence of various nucleophiles (NuH) (Scheme 4). Different NuH groups employed include alcohols (nBuOH), thiols (thiophenols) or electron rich arenes (furan). These were successfully incorporated into a number of indene products 7Nu (Nu = nBuO, ArS and furanyl) upon treatment of 5 with either a Brønsted (MeSO3H) or Lewis (BF3.THF) acid. In all cases 1HNHMR of the crude reaction mixture and the crude mass balance, reflected conversion levels of >75%. However, chromatography on silica gel afforded moderate isolated yields is some cases (40-55%), especially for Nu = nBuOH. Possibly silica gel promotes cleavage of the electron-rich-aryl butyl ether bond in products 7OBu. For reactions involving weaker nucleophiles (Nu = Cl−, nBuOH, furan), undergoing the CNT process, a m-OMe and pOMe (R1 = R2 = OMe), are minimally required in the benzene ring undergoing cyclodehydration. Other dimethoxy (R1 = R3 = OMe: eg 5e and 5n), monomethoxy (R1 or R2 = OMe: eg 5g and 5h) and unsubstitued (5i) systems failed. The m-OMe (R1/3) is required to promote attack upon the carbonyl, whereas the pOMe is required to afford substrate stability under the reaction conditions. In this regard, systems that do not contain a p-OMe (5e, 5n, 5h and 5i) were quite sensitive to the reaction conditions and underwent competitive decomposition at rt, which usually involved fragmentation to form the β-keto ester or amide 13 (Scheme 4, Box). On the other hand, those that contained a p-OMe were stable to the reaction conditions even at elevated temperatures, but required the presence of a m-OMe to cyclize. For reactions involving a stronger nucleophile (Nu = ArSH: 7aSPMP, 7eSPh, 7hSPh), the NAC reaction pathway is most likely (Scheme 2, Path B). The reaction time in these cases were significantly reduced (< 5 h, rt), indicating that both Nu addition to 5 to give 11 and cyclodehydration of 11 to 7Nu are faster than cyclodehydration of 5 to give 9. Also, these reactions did
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not require a p-OMe group and could be achieved with a single m-OMe (7hSPh). However, at least one m-OMe is required, as simple phenyl systems 5 R1-3 = H (eg 5i) do not cyclize under these conditions. The greater substrate scope of these reactions is attributed, in part, to the greater stability of 11 over 5 under the reaction conditions and to higher rate of cyclodehydration of 11 to 7Nu compared to 5 (Scheme 2). To further probe this mechanism, we prepared 11eSPh by reaction of 5e with PhSH under neutral conditions for 3 days (Scheme 5). Subsequent addition of MeSO3H led to cyclodehydration of 11eSPh to 7eSPh within 5 h. This is consistent with the proposed Path B, assuming that MeSO3H catalyses the addition of PhSH to 5e. While the 1H NMR of the crude product 7, prior to chromatography, invariably contained a single ∆a,b double-bond isomer, these occasionally rearranged upon to ∆b,c upon chromatography on silica gel. For all products where 7 Nu = nBuO, no isomerism was apparent during chromatography. For 7 Nu = furanyl, double-bond isomerism during chromatography was minimal (
