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Iodine-Catalyzed Nazarov Cyclizations Jonas J Koenig, Thiemo Arndt, Nora Gildemeister, Jörg-Martin Neudörfl, and Martin Breugst J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01083 • Publication Date (Web): 06 Jun 2019 Downloaded from http://pubs.acs.org on June 7, 2019
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The Journal of Organic Chemistry
Iodine-Catalyzed Nazarov Cyclizations Jonas J. Koenig, Thiemo Arndt, Nora Gildemeister, Jörg-M. Neudörfl, and Martin Breugst* Department of Chemistry, University of Cologne, Greinstraße 4, 50939 Köln, Germany.
[email protected] O X
I2 R1 (5–10 mol%) R2
CH3CN, 25 °C
X = O, CH2
O X R1 R2 19 examples up to 99 %
Abstract The Nazarov cyclization is an important pericyclic reaction that allows the synthesis of substituted cyclopentenones. We now demonstrate that this reaction can be performed under very mild, metal-free reaction conditions using molecular iodine as the catalyst. A variety of different divinyl ketones including aromatic systems undergo the iodine-catalyzed reaction with moderate to very good yields in both polar and apolar solvents. Our mechanistic studies indicate that the Nazarov system is activated through a halogen bond between the carbonyl group and the catalyst and other modes of action like Brønsted-acid or iodonium-ion catalysis are unlikely. Furthermore, addition of iodine to the double bond or a putative iodine-catalyzed cis-trans isomerization of the employed olefins seem not to be an important side reaction here.
Introduction Over the last decade, noncovalent interactions like halogen bonding have grown to become important concepts in different areas of chemistry.1 Halogen bonding is defined as the interaction between a Lewis-acidic region of a halogen atom (typically iodine or bromine) and the lone pair of a Lewis base. Bolm and coworkers applied 1-iodoperfluoroalkanes as halogenbond catalysts for the first time in 2008 in the reduction of 2-substituted quinolines with a Hantzsch ester.2 In the following years, systematic investigations particularly by Huber and 1 ACS Paragon Plus Environment
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coworkers identified polydentate iodinated azolium ions, perfluorinated iodobenzene derivatives, as well as hypervalent iodine(III) compounds as excellent catalysts for the activation of carbon-halogen bonds (Scheme 1).1d, 1e, 3 Similar catalytic systems have also been employed in (hetero)-Diels-Alder reactions,4 imine reduction,5 Michael additions,6 or crossenolate coupling reactions.7
N
CF3(CF2)7–I N R Bolm, 2008
Ph
N I
I
N R
Ph
N N CH3
N
I
I
N H 3C
Ph Ph
Tan, 2014
Huber, 2011
N R
N
N I
CF3
I
Huber, 2015
N R
I
Huber, 2018
Scheme 1: Selected halogen-bond donors used in catalysis.2-3, 3c, 3d, 5
One of the simplest potential halogen-bond donors –molecular iodine– is known to be catalytically active in different reactions for more than 100 years.8 Different mechanisms had been suggested for the catalytic activity including a halogen-bond activation, Brønsted-acid catalysis,9 and activation via the iodonium ion.10 Recently, we were able to show that molecular iodine acts as a halogen-bond donor in different Michael additions (Scheme 2, top). A hidden Brønsted-acid catalysis by HI11 could be ruled out experimentally.12 Furthermore, experimental studies indicated that molecular iodine is equally or even more reactive than traditional Lewis acids like TiCl4 or AlCl3 in these reactions.12b Very recently, molecular iodine also turned out to be an excellent catalyst for the carbonyl-olefin metathesis (Scheme 2, bottom) and is comparable in reactivity to FeCl3.13 However, experimental and computational investigations indicate that in these reactions the catalytically active species might be the iodonium ion rather than a simple halogen-bond activation. 2 ACS Paragon Plus Environment
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The Journal of Organic Chemistry
Iodine-Catalyzed Michael Addition
N H
Ph
5 mol% I2
O
+
Ph
O
CH3CN, 23 °C
N H 93 % after 3 min
Iodine-Catalyzed Carbonyl-Olefin Metathesis CH3 H 3C
O
I2 (10 mol%) + neat, 23 °C, 24 h
H 3C
CH3 O
27 examples 21–96 %
Scheme 2: Recent examples of iodine-catalyzed reactions.12-13
We now wondered whether molecular iodine can also be used in other synthetically important reactions and replace traditional Lewis acids. In this regard, the Nazarov cyclization of divinyl ketones seemed to be the ideal candidate:14 Lewis acids catalyze this transformation very efficiently,15 but Brønsted-acid-catalyzed and organocatalytic variants are also known.16 In 2003, various groups simultaneously reported on polarized Nazarov cyclizations that can be performed under much milder conditions using different metallic Lewis acids like Cu(OTf)2, AlCl3, or Pd(OAc)2 (Scheme 3).15a-d Adding stoichiometric amounts of chiral bis(oxazoline) ligands also resulted in enantioselective transformations. As molecular iodine is an easy to handle solid that is soluble in many organic solvents, a replacement of traditional Lewis acids by I2 could allow milder reaction conditions or reduce potential environmental risks.9,
17
Recently, iodine has already been applied as a catalyst in the related iso-Nazarov reactions with 5 mol% catalyst loading in boiling ethyl acetate (Scheme 3).18 In this mechanistically similar reaction, the alkene attacks the activated carbonyl group and the final cyclopentenone is obtained after isomerization of the double bond. We now report on our results on iodinecatalyzed Nazarov cyclizations and their mechanistic investigations.
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Frontier: O O
Tius: O
Cu(OTf)2 CO2Me (2 mol% ) R
O
O CO2Me
Pd(OAc)2 (20 mol%)
CH3
EtO
R1
AlCl3 (10 mol%)
R2
CH2Cl2 or CH3CN
O
O
O R1
R
O
R1
OEt R3
R2
R2
CH2
R
R
Aggarwal:
O
O EtO
DMSO
25 °C, DCE
Trauner:
O
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CuBr2, AgSbF6 (1 equiv.) chiral PyBOX (1 equiv.)
O R1 R2
CH2Cl2
O OEt R3
up to 88 % ee
This Work:
Gandon, Riveira: I2 (5 mol%)
O H
EtOAc, 120 °C Ph
O
O Ph
X
R1
R2 X = O, CH2
I2 (5–10 mol%)
O X R1
CH3CN, 25 °C R2
Scheme 3: Selected examples for polarized Nazarov and a related iso-Nazarov cyclizations.15ad, 18
Results and Discussion Starting Materials. The divinyl ketones used as the starting materials for the Nazarov cyclization were synthesized following literature-known procedures as summarized in Scheme 4. Lithiation of dihydropyran, reaction with a,b-unsaturated aldehydes, and subsequent oxidation resulted in the Nazarov systems 1,15b while the more polarized structures 3 were obtained from the corresponding b-keto ester and the appropriate aldehyde.15a In addition, Nazarov systems 5 containing the cyclohexene instead of a dihydropyran ring were synthesized in Knoevenagel condensation reactions between suitable aldehydes and the b-keto ester obtained from 1-cyclohexene-1-carboxylic acid.15a, 15g, 19 Typically, only the most stable Econfigured diastereomer was obtained. We have furthermore synthesized the indole derivatives 7 and 9 as potential starting materials with aromatic character modifying known procedures.20 While the corresponding Nazarov products obtained from 7 are key intermediates for the 4 ACS Paragon Plus Environment
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The Journal of Organic Chemistry
synthesis of germination stimulants for seeds of the parasitic plant Orobanche aegyptiaca,21 the Nazarov cyclization of 9b could result in the natural product bruceolline E.22
O
OH 1. tBuLi
O DMP or MnO2
O
O
R
O
R
2. H
R
O
1a–g 36–67 % (over 2 steps) 1. (COCl)2, DMF
O 1. tBuLi
O
OH
2. CO2
HCBr3, LiOH, PTC
O
O
OEt
2. LDA, EtOAc
1. (COCl)2, DMF
O OH
O
O
O
O
O R
pyridine AcOH
O
O OEt
2. LDA, EtOAc
H
H
OEt R 3a–f 23–80 % (over 2 steps) O
R
pyridine AcOH
O
O
O OEt
R 5a (R = 4-MeOC6H4), 45 % 5b (R = (MeO)3C6H2, 74 %
Me O 1. tBuLi, N CH3
H
R
R Me
N O CH3
2. MnO2
7a (R = H), 32 % 7b (R = Me), 26 % O
1. Cl
R Me
Et2AlCl N H
2. NaH, EtOCOCl
O Me R N CO2Et 9a (R = H), 45 % 9b (R = Me), 98 %
Scheme 4: Synthesis of the Nazarov systems (DMP: Dess-Martin periodinane, PTC: phasetransfer catalyst).
Solvent Screening. To test our hypothesis of an iodine-catalyzed Nazarov cyclization, we combined the divinyl ketone 1a with 5 mol% iodine in different solvents (Table 1). After 30 minutes, the reaction mixture was deactivated by filtration through a mixture of Na2S2O3 and Na2CO3 on silica, and the reaction progress was monitored by GC. While no reaction was observed in the absence of a catalyst, fast reactions took place affording the cyclization product 2a in good to excellent yields in the presence of iodine. Isolated product yields were in good agreement with those determined by GC and no alternate reaction products (e.g., addition of
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Table 1. Solvent Influence on the Iodine-Catalyzed Nazarov Cyclization of Divinyl Ketone 1a (0.5 M solutions, 30 min, 25 °C). O O
O
5 mol% I2
O
solvent, 30 min, 25 °C 1a
2a
# Solvent
Yield
#
Solvent
Yield
1 CH3CN
87 % (80 %)[a]
9
EtOAc
97 % (94 %)[a]
2 CH2Cl2
74 % (66 %)[a]
10 toluene
3 CHCl3[b]
85 % (78 %)[a]
11 benzene 79 %
4 Cl(CH2)2Cl
77 %
12 MeOH
