Optimization of Manganese Coupling Reaction for Kilogram-Scale Preparation of Two Aryl-1,3-dione Building Blocks

Article abstract of DOI:10.1021/acs.oprd.7b00241

Aryl-1,3-diones represent a promising new class of herbicidal acetyl-CoA carboxylase (ACCase) inhibitors. The original synthesis of this structural motif employed in the research phase involved a selenium oxide mediated oxidation, the use of diazoacetate and aryl lead reagents, and a low temperature oxidation of an aryl lithium intermediate, so it was not well suited to large scale synthesis. For kilogram scale synthesis of the two aryl-1,3-dione building blocks (3 and 4), we developed an alternative route which employs a manganese or manganese-copper catalyzed alkyl Grignard coupling and a semi-pinacol rearrangement of an epoxide as the key steps. The optimized conditions could be of general interest as scalable methods for the synthesis of 2-alkyl substituted benzaldehydes and of 2-aryl-1,3-diones.

Full text of DOI:10.1021/acs.oprd.7b00241

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Full Paper
Optimization of Manganese Coupling Reaction for Kilogram-
scale Preparation of two Aryl-1,3-dione Building Blocks
Tomas Smejkal, Vijayagopal Gopalsamuthiram, Sujit Kumar Ghorai, Anup M Jawalekar,
Dinesh Pagar, Krishna Sawant, Srinivas Subramanian, Jonathan Dallimore, Nigel Willetts,
James N Scutt, Louisa Whalley, Matthew Hotson, Anne-Marie Hogan, and George Hodges
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00241 • Publication Date (Web): 21 Aug 2017
Downloaded from http://pubs.acs.org on August 21, 2017
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Optimization of Manganese Coupling Reaction for
Kilogramꢀscale Preparation of two Arylꢀ1,3ꢀdione
Building Blocks
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Tomas Smejkal,1*‡ Vijayagopal Gopalsamuthiram,2‡ Sujit K. Ghorai,2 Anup M. Jawalekar,2
Dinesh Pagar, 2 Krishna Sawant, 2 Srinivas Subramanian,2 Jonathan Dallimore, 3 Nigel Willetts,3
James N. Scutt,3 Louisa Whalley, 3 Matthew Hotson, 3 Anne-Marie Hogan,3† George Hodges,3
1Syngenta Crop Protection AG, Schaffhauserstrasse, CHꢀ4332 Stein, Switzerland; 2Syngenta
Research and Technology Centre, Santa Monica Works, Corlim, Ilhas, Goa, Indiaꢀ403110;
3Syngenta Ltd., Jealott's Hill International Research Centre, Bracknell, Berkshire RG42 6EY,
United Kingdom;
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Table of Contents Graphic:
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[Mn]
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H+
3 R = Me
4 R = Et
[Mn/Cu]
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Abstract: Arylꢀ1,3ꢀdiones represent a promising new class of herbicidal acetylꢀCoA
carboxylase (ACCase) inhibitors. The original synthesis of this structural motif employed in the
Research phase, involved a selenium oxide mediated oxidation, the use of diazoacetate and aryl
lead reagents, and a low temperature oxidation of an aryl lithium intermediate so was not well
suited to large scale synthesis. For kilogram scale synthesis of the two arylꢀ1,3ꢀdione building
blocks (3 and 4), we developed an alternative route which employs a manganese or manganeseꢀ
copper catalyzed alkyl Grignard coupling and a semiꢀpinacol rearrangement of an epoxide as the
key steps. The optimized conditions could be of general interest as scalable methods for the
synthesis of 2ꢀalkyl substituted benzaldehydes and of 2ꢀarylꢀ1,3ꢀdiones.
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Keywords: Manganese, Copper, Grignard coupling, Semiꢀpinacol, Arylꢀ1,3ꢀdione, ACCase
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INTRODUCTION
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Inhibitors acting on acetylꢀCoA carboxylase (ACCase) are among the most important
herbicidal modes of action for the control of grass weeds. Pinoxaden (1, Figure 1), the active
ingredient of AXIALTM an herbicide that was introduced by Syngenta in 2006. Pinoxaden is a
procidal form of Pinoxaden acid (the active principle) which contains the unique 2 arylꢀ1,3ꢀdione
moiety (Figure 1).1, 2
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Figure 1. Structure of Pinoxadene 1, Pinoxadene acid 2 and 2ꢀarylꢀ1,3ꢀdione design principle.
2-Aryl-1,3-dione
Pinoxaden, 1
Active principle
Pinoxaden acid, 2
As a part of our Herbicide Research program exploring novel 2ꢀarylꢀ1,3ꢀdione structures,
kilogram scale synthesis of two building blocks (3, R = ethyl and 4, R = methyl, Scheme 1) was
required. These phenolic building blocks were designed to enable broad exploration of the
structure activity relationship around the aromatic core by further modifications (including
alkylation, arylation and triflation followed by various metal couplings).3
Scheme 1. Aryl-1,3-diones building blocks 3 and 4, some derivatization possibilities.
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Nu-H
/[Pd]
Alkyl-X
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R = Me
R = Et
3
4
Aryl-B(OH)2
/[Pd]
Aryl-X
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FIRSTꢀGENERATION SYNTHESIS
The discovery synthesis of building blocks 3 and 4 started from commercially available
2,2,5,5ꢀteramethyltetrahydrofuranꢀ3ꢀone (10). It was oxidized using selenium oxide in ethanol to
give the corresponding dione 11.4 Ring expansion using diazonium acetate, followed by
decarboxylation gave 2,2,6,6ꢀ tetramethyltetrahydropyraneꢀ3,5ꢀdione (12) in 50ꢀ60% yield.5
Unfortunately, direct arylation of building block 12 using palladium catalyzed conditions6
proved only moderately successful, probably due to high steric hindrance of both dione and aryl
bromide coupling partners. The most robust method for the direct coupling of orthoꢀsubstituted
aryls was found to be an unusual aryl lead cross coupling reaction using conditions reported by
Morgan and Pinhey.7, 8 Aryl lead reagents had to be prepared from the corresponding aryl
boronic acid using lead tetraacetate and catalytic mercury(II) acetate in chloroform.7 The
arylation itself was performed using a large excess of N,Nꢀdimethylꢀ4ꢀaminopyridine in a 4:1
chloroform / toluene mixture. Finally, after deprotonation of the dione moiety, low temperature
bromineꢀlithium exchange followed by air oxidation provided the required building blocks 3 and
4 (Scheme 2, only 4 shown).
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Although the aryl lead coupling route was relatively high yielding and short, scale up issues
throughout the synthesis precluded any work beyond gram scale. We therefore focused on
designing a novel synthetic approach.
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Scheme 2. Discovery Chemistry Synthesis of Aryldione Building Block 4
1. N2CHCOOEt, BF3.Et2O, RT
SeO2, ethanol
2. DMSO/water 120°C
50-60%
80%
10
11
12
13
5 eq. DMAP,
CHCl3/Toluene (4:1)
1. i-PrMgCl, n-BuLi, -78°C
2. air, HCl
60-80%
50-60%
14
4
SECONDꢀGENERATION SYNTHESIS
It was envisioned that the arylꢀ1,3ꢀdiones 3 and 4 could be obtained by semiꢀpinacol
rearrangement of the corresponding epoxyꢀketone 15 and 16.9, 10 Our previous experience of this
rearrangement showed that is relatively general method favoring arylꢀ1,3ꢀdiones, over the
isomeric 1,2ꢀdiones, through a preferential acyl transfer mechanism under protic or Lewis acid
catalysis.8 The required epoxide starting materials (compounds 15 and 16, Scheme 2) could in
turn be synthesized by condensation of furanone 10 with aldehydes 17 or 18 followed by
epoxidation or alternatively by Darzens reaction of bromoꢀfuranone 19 and the corresponding
aldehyde (Scheme 3).8 Accordingly, our first goal was to find an efficient synthesis of aldehyde
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building blocks 17 and 18. To this end we focused on an interesting manganese coupling reaction
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which was supported by literature precedent.11
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Scheme 3. Retrosynthesis of Aryl-tetramethylpyrandione via Semi-pinacol Rearrangement,
Condensation/Epoxidation and Darzens approaches
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10
R = Me
R = Et
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18
R = Me
R = Et
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R = Me
R = Et
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4
19
Manganese catalyzed coupling of Grignard reagents with various orthoꢀ and paraꢀsubstituted
benzaldehyde imines has been described by Cahiez as a very efficient route to substituted
benzaldehydes (compound 20 to 21, Scheme 4).11 Furthermore, electron rich substrates such as
4ꢀbromoꢀanisole were also shown to undergo the same transformation albeit with reduction
predominating in reactions performed with Grignard reagents possessing βꢀhydrogens
(compound 22 to 23 and 24, Scheme 4).12
Scheme 4. Manganese catalyzed coupling and reduction of aromatic substrates using n-
butyl Grignard reagent.12
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n-BuMgBr, MnCl2 (10mol%)
THF, 0°C/RT
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, X = Br, Cl, F, OMe
, >90%
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n-BuMgBr, MnCl2 (1mol%)
THF, RT
, 20%
, 50%
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In an initial test reaction, addition of an excess of ethyl magnesium bromide to 25 without
manganese catalyst gave only a trace amount of the desired product 18 (Table 1, Entry 1). The
same reaction in the presence of anhydrous MnCl2 (10mol %) gave clean reaction providing a
4:1 – 5:1 mixture of the desired coupling product 18 and byꢀproduct 26 (Table 1, Entry 2). Best
results regarding the 18 vs. 26 selectivity were obtained adding ethyl magnesium bromide slowly
(over 45min) and vigorous stirring to limit localised concentration of the Grignard reagent.
Reaction in less polar solvent systems (Toluene/THF or MeTHF/THF) led to lower selectivity
(Table 1, Entry 3). Reaction under atmosphere of ethylene gave improved selectivity (Table 1,
Entry 4). And finally, addition of methyl Grignard (1.5 eq.) followed by the addition of ethyl
Grignard (1.5 eq.) gave improved selectivity of the ethyl Grignard coupling (8:1 = coupling:
reduction) and no coupling of methyl Grignard at all (Table 1, Entry 5). Therefore, MnCl2 is
involved both in the formation of the desired product and reduction byꢀproduct. Reduction byꢀ
product 26 may be formed via βꢀhydrogen elimination of ethylꢀmanganese species and aryl
bromide 25 reduction according the mechanism described by Cahiez.12 A vacant coordination
site on manganese next to the ethyl substituent is needed for βꢀhydrogen elimination, and so the
addition of coordinating reagents (such as ethylene, solvent molecule or methyl Grignard) is
presumably improving the reaction selectivity by blocking this site. Despite, significantly
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improving the reaction selectivity we could not improve it further and challenges in separating
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compounds 18 and 26 led us to consider an alternative approach.
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Table 1. Optimization of Ethyl Grignard Cross-Coupling Reaction – Substrate 25
1. Reagent, Catalyst, Additive
THF, 0oC-rt, 18h
2. 6M HCl
Br
H
+
N
O
O
HO
HO
HO
n-Bu
25
18
26
Entry Reagent
Catalyst
Additive
ꢀ
Conv. 25a
Ratio
of
18/26b
1
EtMgBr
ꢀ
<20%
nd
(300 mol%)
EtMgBr
2
MnCl2 (10mol%)
MnCl2 (10 mol%)
MnCl2 (10 mol%)
MnCl2 (10 mol%)
ꢀ
ꢀ
100%
100%
100%
100%
4:1ꢀ5:1
~2.5:1
8:1
(300 mol%)
EtMgBr
3c
4
(300 mol%)
EtMgBr
Ethylene (1 bar)
(300 mol%)
EtMgCl
5d
MeMgCl
8:1
(150 mol%)
(150mol%)
a HPLC area (%), nd = not determined (<5% yield of 18/26) b 1H NMR ratio in crude product, c
Alternative reaction solvents: Toluene/THF (2:1) or MeTHF/THF (3:1), d Addition of methyl
Grignard followed by ethyl Grignard reagent, no coupling product of methyl Grignard observed.
We turned our attention to an alternative substrate 27, which could be easily accessed form 1,4ꢀ
dimethoxybenzene. Coupling of 27 with ethyl Grignard provided 28. As before there was no
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conversion to the desired product in the absence of the catalyst (Table 2, Entry 1). In the
presence of anhydrous MnCl2 (10%) clean conversion to the desired product was observed with
no reduction byꢀproduct, but the reaction was unfeasibly slow (Table 2, Entry 2). Pleasingly,
addition of lithium chloride (2 eq.) significantly increased the reaction rate and provided the
desired coupling product in excellent yield (Table 2, Entry 3).13
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Table 2. Optimization of Ethyl Grignard Cross-Coupling Reaction – Substrate 27
1. EtMgBr (200 mol%)
Catalyst, Additive
THF, Conditions
2. 6M HCl
27
28
Entry
1
Catalyst
ꢀ
Additive
ꢀ
Conditions
0°C 30min,
RT 15h
Conv.27a
Yield 28a
<10%
0%
2
3
MnCl2
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0°C 30min,
RT 15h
25%
21%
(10 mol%)
MnCl2
LiCl
0°C 30min,
RT 15h
100%
>90%
(10 mol%)
(200 mol%)
a HPLC area (%)
For our second target, aldehyde building block 17, selective introduction of a methyl group was
required. Crossꢀcoupling of a methyl group on an aromatic core is a wellꢀestablished
transformation with numerous coupling protocols having been developed.14 Approaches utilising
methyl boron derivatives have the major drawback of high cost and poor availability on large
scale. Alternatively, dimethyl zinc and trimethyl aluminium are highly pyrophoric making the
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large scale handling of the reagent troublesome. From the scale up and cost point of view the
most preferable would be the direct use of methyl Grignard reagent (Table 3).
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Table 3. Organometallic methyl equivalents
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Reagent
Costa (scale)
methylboronic acid
1’820$/mol (5g)
954$/mol (250g)
4’475$/mol (5g)
168$/mol (100g)
86$/mol (18L)
trimethylboroxine
potassium methyltrifluoroborate
trimethylaluminum (neat)
trimethylaluminum (2M in toluene)
dimethylzinc (2M in toluene)
2’225$/mol (500mL)
methylmagnesium bromide (3M in 29$/mol (18L)
diethyl ether)
a Cost $/mol and the largest scale available in Aldrich catalogue http://www.sigmaaldrich.com
on 13.03.2017.
We started our investigation by adding an excess of methyl magnesium bromide to a stirred
mixture of substrate 25 and anhydrous MnCl2 catalyst (10 mol%). After increasing the reaction
temperature to reflux only a trace of the desired product 17 was formed (Table 4, Entry 1). Using
an alternative catalyst, copper chloride (10 mol%), no formation of the desired product 17 was
observed and mostly unreacted starting material was recovered (Table 4, Entry 2). Interestingly,
combining both metals gave 41% of the desired coupling product 17 after 20 hours at room
temperature (Table 4, Entry 3). The yield was further improved by running the reaction at reflux
for 1.5 hours (Table 4, Entry 4). Manganeseꢀcopper catalysis is known, but to the best of our
knowledge has previously been employed only in sp3ꢀsp3 couplings.15 Reaction employing
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methyl magnesium bromide solution in MeTHF was slightly less clean, giving up to 20% of
dehalogenation byꢀproduct (Table 4, Entry 5).
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Table 4 Optimization of Methyl Grignard Cross-Coupling Reaction – Substrate 25
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1. Reagent, Catalyst,
Conditions
2. 6M HCl
25
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Entry Reagent
Catalyst
MnCl2
Conditons
0°C, 1h
Conv. 25a
<10%
17a
1
2
3
MeMgBr in Et2O
Trace
(300 mol%)
(10 mol%)
CuCl
Reflux, 1.5h
0°C, 1h
MeMgBr in Et2O
(300 mol%)
<10%
80%
0
(20 mol%)
RT/20h
MeMgBr in Et2O
(300 mol%)
MnCl2
mol%)
(10 0°C, 1h
41%
RT/20h
CuCl
(10 mol%)
MnCl2
4
5
MeMgBr in Et2O
(300 mol%)
0°C, 1h
100%
100%
95%
80%
(20 mol%)
CuCl
Reflux, 1.5
h
(10 mol%)
MeMgBr in MeTHF MnCl2
(300 mol%) (20 mol%)
0°C, 1h
Reflux, 1.5
h
CuCl
(10 mol%)
a HPLC area (%)
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With the required aldehyde building block in hand we turned our attention to the optimization
and scale up of the remaining reaction sequence (Scheme 5). Dimethoxy benzaldehyde was
condensed with nꢀbutyl amine using sodium sulfate as dehydrating agent to provide imine 27 in
quantitative yield. The crude product was concentrated, reꢀdissolved in THF and added directly
over a period of 30min to a stirred mixture of anhydrous MnCl2 (10 mol%), lithium chloride (2
eq.) and ethyl magnesium chloride (2eq.) in THF at 0ꢀ5°C. After 15 hours at room temperature,
the reaction was quenched and hydrolyzed providing aldehyde intermediate 28 in 88% yield.
Darzens reaction of 28 and bromoꢀfuranone 19 gave us 63% of epoxyaldehyde 30.
Rearrangement to dione 31 was realized using concentrated sulphuric acid – toluene in 46%
yield. Final, deprotection using aq. hydrobromic acid / acetic acid mixture provided dione
building block 4 in 66% yield.
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Scheme 5. Optimized Second Generation Route to 4
1. EtMgBr, 10 mol% MnCl2,
2eq LiCl, THF
2. water, HCl
n
-BuNH2, DCM,
Na2SO4
tBuOK, DMSO
63%
19
99%
88%
29
27
28
DCE, H2SO4
46%
HBr, Acetic acid
66%
30
31
4
In the second sequence 3ꢀhydroxybenzaldehyde (32) was brominated using bromine in
dichloromethane. Condensation with nꢀbutyl amine gave imine 25, which was successfully
isolated in this case. The coupling reaction was performed by adding methyl magnesium bromide
(2.2M in diethylether) to a stirred suspension of 25, anhydrous MnCl2 20 mol% and copper (I)
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chloride (10 mol%) in THF at ꢀ10 to 0°C. After the addition, the reaction mixture was brought to
reflux over 1h and maintained at reflux for additional 2 hours. After quench and acidic
hydrolysis the aldehyde building block 17 was isolated in 80% yield. The Darzens reaction was
problematic with the unprotected phenol group and so we opted for an alternative sequence
consisting of a condensation reaction followed by epoxidation. Condensation with 2,2,5,5ꢀ
tetramethyltetrahydrofuranꢀ3ꢀone (10) using sodium methoxide in methanol yielded chalcone 34
in 79% yield. Epoxidation was realized by slow addition of hydrogen peroxide to a mixture of
34, sodium tungstate catalyst, sodium hydroxide and phase transfer catalyst in a waterꢀethanol
mixture. Spiroepoxide 15 was rearranged to the dione 3 using dichloromethane / sulphuric acid
in 70% yield. On a smaller scale, the rearrangement of 15 to 3 was also found to be successful
with Amberlystꢀ15 ion exchange resin in comparable yields.
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Scheme 6. Optimized Second Generation Route to 3
1. MeMgBr, 20% MnCl2,
10% CuCl, THF
n
-BuNH2, DCM,
Br2, DCM
74%
Na2SO4
2. water, HCl
74%
80%
32
10
33
25
17
H2O2, 2 mol% Na2WO4
15 mol% CTAB
ethanol, water
DCM, H2SO4
NaOMe, MeOH
79%
75%
70%
(OR Amberlyst-15,
DCM, 72%)
34
15
3
In conclusion a straightforward synthesis of two arylꢀ1,3ꢀdione building blocks was realized on
kilogram scale employing manganese and manganeseꢀcopper catalyzed alkyl Grignard couplings
and a semiꢀpinacol rearrangement of an epoxide as the key steps. Our optimized ethyl and
methyl Grignard coupling protocols could find applications in the synthesis of other 2ꢀalkyl
substituted benzaldehydes and related transformations.
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All reagents were obtained from commercial sources and used without further purification
unless otherwise stated. Commercial grade anhydrous MnCl2 was used as received unless
otherwise stated. All reactions were carried out under a nitrogen atmosphere unless otherwise
stated. All glassware was dried and purged with nitrogen before use. Reactions were monitored
by Agilent 1200 Series HPLC and Agilent ESI LCMS systems, detection was by UV at 220 nm
unless otherwise specified.
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All H NMR and C NMR spectra were recorded on a Bruker 400 MHz spectrometer. Agilent
QꢀTOF instrument. 4ꢀbromoꢀ2,2,5,5ꢀtetramethylꢀtetrahydrofuranꢀ3ꢀone (19) was prepared
according to literature precedent.16
(E)-N-butyl-1-(2,5-dimethoxyphenyl)methanimine (27). At 25°C anhydrous sodium
sulphate (8.60 kg) was added to a suspension of 2,5ꢀmethoxy benzaldehyde (5.00 kg, 30.08 mol)
in dichloromethane (50.0 L) followed by addition nꢀbutyl amine (2.30 kg, 31.45 mol) over a
1
period of 1 hr. The reaction mixture was stirred at 25°C and monitored by H NMR. After
complete consumption of starting material (12h), the reaction mass was filtered to remove
sodium sulphate and the filter cake was washed with dichloromethane (25.0 L). The combined
organic extract was concentrated to afford (E)ꢀNꢀbutylꢀ1ꢀ(2,5ꢀdimethoxyphenyl)methanimine
1
(6.60 kg, 99% NMR purity, 99% yield) as a yellow semiꢀsolid. H NMR (400 MHz, CDCl3): δ
0.94 (t, 3H, J = 7.2 Hz), 1.35ꢀ1.41 (m, 2 H), 1.63ꢀ1.67 (m, 2 H), 3.60ꢀ3.63 (m, 2 H), 3.80 (2s, 6
H), 6.85 (d, J = 8.8 Hz, 1 H), 6.92 (dd, J = 8.8 Hz & 3.2 Hz, 1 H) 7.48 (d, J = 3.2 Hz, 1 H), 8.60
13
(s, 1 H); C NMR (101 MHz, CDCl3): δ 13.8, 20.4, 33.1, 55.7, 56.0, 61.6, 110.4, 112.6, 118.3,
125.3, 153.1, 153.7, 156.4 Note: Product skin and eye irritant, moisture sensitive. The crude
product was directly used in the following step.
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2-ethyl-5-methoxy-benzaldehyde (28). Anhydrous MnCl2 (188 g, 1.49 mol) and lithium
chloride (1.25 kg, 29.49mol) were suspended in in anhydrous tetrahydrofuran (50.0 L), stirred at
25°C for 30 min and cooled to ꢀ10°C. Then ethyl magnesium bromide solution in
tetrahydrofuran (15.2 L, 2.0 M solution, 30.4 mol) was added over a period of 30 min. (internal
temperature ꢀ10°C to 0°C). The reaction mass was stirred for 30 min and to the Grignard
reaction mass, a solution of imine 27 (3.30 kg in 5.0 liters of tetrahydrofuran, 14.91 mol) was
added at 0ꢀ5°C over a period of 30 min. The reaction mixture was bought to 25°C during 30
minutes and stirred at this temperature for additional 15h. The reaction was monitored by
HPLC. The reaction mass was then eventually cooled to 0°C and excess of Grignard was
quenched with 2.2 L of acetone. To the above reaction mass was further added saturated
ammonium chloride solution (10.0 L) followed by 6M aqueous hydrochloric acid (10.0 L). The
reaction mixture was stirred for 30 min at 25°C. The reaction mass was extracted with ethyl
acetate (3 x 5.0 L) and the combined organic extract was washed with saturated brine (2 X 10 L).
Concentration of the organic layer afforded 2ꢀethylꢀ5ꢀmethoxyꢀbenzaldehyde (28) (2.15 kg, 95%
NMR purity, 83% yield) as a yellow liquid. 1H NMR (CDCl3, 400 MHz,): δ 1.25 (t, 3H, J = 7.7
Hz), 3.00 (q, 2H, J = 7.7 Hz), 3.85 (s, 3 H), 7.09 (dd, 1H, J = 8.4, 2.9 Hz), 7.21 (d, 1H, J = 8.4
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Hz), 7.36 (d, 1H, J = 2.9 Hz), 10.30 (s, 1 H); C NMR (CDCl3, 101 MHz): δ 16.9, 24.6, 55.5,
113.5, 121.2, 131.4, 134.1, 139.7, 158.1, 191.7; HRMS m/e 165.0911 [(M+H)+, calcd for
C10H12O2 165.0910] The crude product was directly used in the following step.
2-(2-ethyl-5-methoxy-phenyl)-5,5,7,7-tetramethyl-1,6-dioxaspiro[2.4]heptan-4-one (30).
To a solution of potassium tꢀbutoxide (1.20 kg, 10.69 mol) in dimethyl sulfoxide (4.4 L),
2,2,5,5ꢀtetramethylꢀ4ꢀbromo tetrahydrofuranꢀ3ꢀone (19) (1.78 kg, 8.05 mol) was added dropwise
maintaining the reaction mass below 20°C. The reaction mass was stirred for 1 hr and after that
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time a solution of 2ꢀethylꢀ5ꢀmethoxyꢀbenzaldehyde (28) (885g, 5.12 mol) in DMSO (4.5 L) was
added slowly during 30 minutes. The reaction mass was warmed to 25°C and stirred for 15 hr.
The reaction was monitored by HPLC. The reaction was diluted with water (50.0 L) and
extracted with tꢀbutyl methyl ether (3 x 10.0 L). The combined organic layer was washed with
brine (5 L) and concentrated to afford crude product (1.9 Kg). The crude mass was adsorbed on
silica and chromatographed over silica using ethyl acetateꢀcyclohexane as solvent to afford
diastereomeric mixture of expected product (2ꢀ(2ꢀethylꢀ5ꢀmethoxyꢀphenyl)ꢀ5,5,7,7ꢀtetramethylꢀ
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1,6ꢀdioxaspiro[2.4]heptanꢀ4ꢀone, 1.03 Kg, 63% yield). Major isomer H NMR (CDCl3, 400
MHz,): δ 1.08 (s, 3H), 1.25 (t, 2H, J = 8 Hz), 1.34 (s, 3H), 1.40 (s, 3H), 1.51 (s, 3H), 2.57ꢀ2.69
(m, 2H), 3.65 (s, 3H), 4.50 (s, 1H), 6.83 (dd, 2H, J = 8 Hz, 4 Hz), 7.06 (d, 1H, J = 8 Hz), 7.17 (d,
1H, J = 4Hz); 13C NMR (CDCl3, 101 MHz): δ 14.9, 24.7, 25.9, 25.9, 26.1, 26.1, 55.4, 64.0, 70.5,
75.1, 78.5, 111.6, 115.2, 128.7, 130.7, 132.9, 157.3, 211.2; HRMS m/e 305.1764 [(M+H)+, calcd
for C10H12O2 305.1764]
4-(2-ethyl-5-methoxy-phenyl)-2,2,6,6-tetramethyl-
tetrahydropyran-3,5-dione (31). Concentrated sulphuric acid (10.0 L) was added to a solution
of spiroepoxide 30 (10.0 kg, 32.85 mol) in toluene (80.0 L) at 0ꢀ5°C. The reaction mixture was
warmed to 25°C and stirred at this temperature for 16 hr. The conversion monitored by LCꢀMS.
The reaction mass was quenched by pouring into iceꢀwater (50.0 L). The organic layer was
separated. The aqueous layer was neutralized with sodium bicarbonate to a pH of ~6ꢀ7 and
extracted with ethyl acetate (3 x 20.0 L). The combined organic extract (toluene & ethyl acetate)
was washed with brine (20.0 L) and concentrated under vacuum. The crude product was purified
by chromatography using silica as stationery phase and cyclohexaneꢀethyl acetate as mobile
phase to afford pure 4ꢀ(2ꢀethylꢀ5ꢀmethoxyꢀphenyl)ꢀ2,2,6,6ꢀtetramethylꢀtetrahydropyranꢀ3,5ꢀ
1
dione (4.60 Kg, 46% yield). H NMR (CDCl3, 400 MHz,): δ 1.09 (t, 3H, J = 7.5 Hz), 1.48 (s, 3
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H), 1.49 (s, 3 H), 1.60 (s, 6 H) 2.33ꢀ2.41 (m, 2 H), 3.79 (s, 3 H), 5.71 (s, 1 H), 6.60 (d, J = 2.6
5
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Hz, 1 H), 6.88ꢀ6.95 (m, 1 H) 7.23ꢀ7.30 (m, 1 H); C NMR (CDCl3, 101 MHz): δ 15.3, 25.4,
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27.5, 27.8, 28.5, 28.8, 55.4, 72.5, 78.4, 110.9, 115.1, 116.6, 129.0, 130.5, 136.9, 158.3, 171.7,
196.9; HRMS m/e 305.1752 [(M+H)+, calcd for C18H24O4 305.1747].
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4-(2-ethyl-5-hydroxy-phenyl)-2,2,6,6-tetramethyl-tetrahydropyran-3,5-dione (4). Acetic
acid (27.3 L) and aq. hydrobromic acid (48%, 27.3 L) was added sequentially to a stirred
solution of 4ꢀ(2ꢀethylꢀ5ꢀmethoxyꢀphenyl)ꢀ2,2,6,6ꢀtetramethylꢀtetrahydropyranꢀ3,5ꢀdione (31)
(1.90 kg, 6.24 mol) at 25ꢀ30˚C. The reaction mixture was warmed to 100°C and stirred at this
temperature for 7 hr. The reaction progress was monitored by LCꢀMS. At the end of the
reaction, the reaction mass was cooled to 25°C, diluted with water (150.0 L) and extracted with
ethyl acetate (3 x 20.0 L). The combined organic extract was washed with brine (10.0 L) and
concentrated. The crude product was purified by chromatography using silica as stationery phase
and cyclohexaneꢀethyl acetate as mobile phase to afford pure 4ꢀ(2ꢀethylꢀ5ꢀhydroxyꢀphenyl)ꢀ
1
2,2,6,6ꢀtetramethylꢀtetrahydropyranꢀ3,5ꢀdione (1.20 kg, 66% yield). H NMR (CDCl3, 400
MHz,): δ 1.06 (t, 3H, J = 7.5 Hz), 1.41 ꢀ 1.53 (m, 6H), 1.53 ꢀ 1.70 (m, 6H), 2.25ꢀ2.45 (m, 2H),
13
6.11 (bs, 1H), 6.31 (d, 1H, J = 2.6 Hz), 6.55ꢀ6.75 (bm, 2H) 7.10 (d, 1H, J = 8.4 Hz); C NMR
(CDCl3, 101 MHz): δ 15.3, 25.4 , 27.8 (m, 2C) 28.6 (m, 2C), 72.7, 78.3, 110.8, 117.0, 118.6,
128.0, 130.4, 135.9, 154.9, 173.2, 198.6; HRMS m/e 291.1583 [(M+H)+, calcd for C17H22O4
291.1591].
2-bromo-5-hydroxy-benzaldehyde (33). Bromine (1.468 L, 28.66 mol, 1 eq.) was added to a
suspension of 3ꢀhydroxy benzaldehyde (3.5 kg, 17.4 mol) in dichloromethane (26.5 L) over a
period of 3 hr at ꢀ5 to 0°C. The reaction mass was brought to 25°C and stirred at this
temperature for 12 hr. The reaction was monitored by HPLC and TLC. The reaction mass was
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purged with nitrogen at room temperature to remove dissolved hydrobromic acid. The reaction
mass was cooled to 0°C and was filtered and suck dried on a glass Neutche filter. The filter cake
was reꢀsuspended in saturated sodium bicarbonate (50.0 L) and stirred at room temperature for 3
hr. The product suspension was filtered over a Neutche filter and washed with water (10.0 L).
The filtered product was air dried to moisture content less than 2% giving 2ꢀbromoꢀ5ꢀhydroxyꢀ
benzaldehyde (4.3 Kg, 97% purity by HPLC 258 nm, 74% yield). Note: Product is skin and
eye irritant. The analytical data correspond to those reported in literature.17
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4-bromo-3-[(E)-butyliminomethyl]phenol (25). 2ꢀBromoꢀ5ꢀhydroxy benzaldehyde (4.3 Kg,
21.39 mol, considered to be 100% pure) was suspended in dichloromethane (64.5 L) and stirred
at 5°C. Anhydrous sodium sulphate (6.07 Kg, 42.78 mol, 2 eq.) was added to the reaction
mixture followed by slow addition of nꢀbutyl amine (3.20 L, 2.37 Kg, 32.08 mol, 1.56 eq.) at 0 ꢀ
5°C over a period of 1 h. The reaction mass was brought to 25°C and stirred at this temperature
for 12 hr. The reaction progress was monitored by GC. The reaction mass was filtered off to
remove sodium sulphate and the filter cake was washed with ethyl acetate (25.0 L). The
combined filtrate was concentrated to afford a semiꢀsolid. The crude product was suspended in
toluene (50.0 L) and ~50% of toluene was distilled off under reduced pressure to remove
unreacted amine and any residual moisture. The reaction mixture was cooled to 25°C and the
product was filtered on a glass Neutche filter. The solid was washed with fresh toluene (5.0 L)
and then with cyclohexane (2 x 5.0 L). The solid mass was dried under vacuum to provide 4ꢀ
bromoꢀ3ꢀ[(E)ꢀbutyliminomethyl] phenol (3.90 kg, 97% NMR purity, 74% yield).
Note:
Product skin and eye irritant, moisture sensitive upon prolong exposure.
1H NMR
(DMSOꢀd6, 400 MHz,): δ 9.78 (brs, 1H), 8.46 (s, 1H), 7.42ꢀ7.39 (m, 2H), 6.82ꢀ6.79 (m, 1H),
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3.57 (t, 2H, J = 8 Hz), 1.61ꢀ1.54 (m, 2H), 1.32ꢀ1.27 (m, 2H), 0.89 (t, 3H, J = 8 Hz); C NMR
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(DMSOꢀd6, 101 MHz): δ 158.8, 156.9, 134.7, 133.6, 119.9, 114.5, 112.7, 60.3, 32.5, 19.9, 13.7
HRMS m/e 198.94 [(MꢀnBu+H)+, calcd for C7H6BrNO 198.96].
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5-hydroxy-2-methyl-benzaldehyde (17). Anhydrous THF (25.0 L) was added to imine 25
(2.55 kg, 9.66 mol) and the suspension was stirred at 25°C. Then anhydrous MnCl2 (250 g, 1.98
mol, freshly dried at 80°C under vacuum for 2 hr) and copper (I) chloride (98.5g, 0.995mol)
were added. The reaction mass was cooled to ꢀ10°C, and then 2.2 M methyl magnesium
bromide solution in diethyl ether (13.57 L, 29.85mol) was added over a period of 1 hr
(temperature between ꢀ10°C and 0°C). The reaction mass was slowly bought to reflux
temperature over a period of 1 hr and maintained at reflux temperature for 2 hr. The reaction
progress was monitored by HPLC. The reaction mass was cooled to 0°C and excess of methyl
magnesium bromide reagent was quenched with acetone (2.2 L). The reaction mass was further
quenched with 1M hydrochloric acid ( ~40 L) till the reaction mass was acidic (pH ~1). The
organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 20.0 L).
The combined organic extract was washed with saturated brine (2 x 10.0 L) and concentrated to
give brown solid (1.7 Kg). The crude product was purified by column chromatography using
cyclohexane : ethyl acetate (0ꢀ30%) to provide 1.29 Kg of solid which was further slurried in
2.6 L of DCM ꢀ Petrolether (1:1), filtrated and dried to give 5ꢀhydroxyꢀ2ꢀmethylꢀbenzaldehyde
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(1.08 kg, 98% NMR purity, 80% yield). H NMR (DMSOꢀd6, 400 MHz): δ 10.15 (s, 1H), 9.65
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(s, 1H), 7.19 (s, 1H), 7.12 (d, 1H, J = 8.0 Hz), 6.96 (d, 1H, J = 8 Hz), 2.48 (s, 3H); C NMR
(DMSOꢀd6, 101 MHz): δ 193.2, 156.0, 134.8, 133.0, 130.7, 17.9, two carbon signals not
observed; HRMS m/e 136.045 [(M)+, calcd for C8H8O2 136.052].
(4)-4-[(5-hydroxy-2-methyl-phenyl)methylene]-2,2,5,5-tetramethyl-tetrahydrofuran-3-
one (34). To a solution of 2,2,5,5ꢀtetramethyltetrahydrofuranꢀ3ꢀone (10) (2.48 kg, 17.4 mol,
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1.93 eq.) in methanol (3.7 L) was added sodium methoxide in methanol (25 mass %, 7.35 L,
32.13 mol) at 0°C over a period of 35 min and stirred at 0°C for additional 5 min. A solution
of 5ꢀhydroxyꢀ2ꢀmethylꢀbenzaldehyde (1.25 kg, 9.00 mol) in methanol (8.8 L) was added to the
reaction mass at 0°C over a period of 1 hr. The reaction mass was slowly bought to reflux
temperature ~65°C and refluxed for 4 hr. The reaction progress was monitored by HPLC. The
reaction was cooled to 20°C, acidified with 2M hydrochloric acid (4.4 L) and stirred at room
temperature for 12h. The suspension formed was suction filtered and the filter cake was washed
with water (~5.0 L, until neutral pH). The crude product was dissolved in TBME (10.0 L), water
phase was separated and TBME layer was evaporated to yield 1880 g of pure product 34 (1880
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g, 79% yield). H NMR (DMSOꢀd6, 400 MHz): δ 9.39 (s, 1H), 7.44 (s, 1H), 7.03 (d, 1H, J = 8
13
Hz), 6.69 (d, 1H, J = 8 Hz), 6.68 (s, 1H), 2.08 (s, 3H), 1.30 (s, 6H), 1.23 (s, 6H); C NMR
(DMSOꢀd6, 101 MHz): δ 206.9, 155.1, 140.7, 134.9, 134.3, 131.1, 126.4, 116.0, 114.9, 79.2,
78.8, 29.8, 26.1, 18.9, one carbon signal not observed; HRMS m/e 260.13 [(M)+, calcd for
C16H20O3 260.14].
2-(5-hydroxy-2-methyl-phenyl)-5,5,7,7-tetramethyl-1,6-dioxaspiro[2.4]heptan-4-one (15).
To a solution of (4E)ꢀ4ꢀ[(5ꢀhydroxyꢀ2ꢀmethylꢀphenyl)methylene]ꢀ2,2,5,5ꢀtetramethylꢀtetrahydroꢀ
furanꢀ3ꢀone (1.00 kg, 3.84 mol) in ethanol (5.7 liter) and water (5.7 liter) at 25°C, was added
1M NaOH solution (3.96 L, 3.96 mol) over a period of 15 min. To this alkali solution, sodium
tungstate dehydrate (2.28 g, 0.0076 mol, 0.002 eq.) and cetyl trimethyl ammonium bromide (212
g, 0.576 mol, 0.15 eq.) were added and the reaction mass was heated to 50°C. Hydrogen
peroxide (342 ml, 40% in water, 0.576 mol, 0.15 eq.) was added slowly over a period of 15 min
at 50°C using a dosing pump (exothermic) and the reaction mixture was stirred at 50°C for
additional 15min. The reaction conversion was monitored by HPLC. The reaction mixture was
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quenched with aqueous sodium metaꢀbisulphite solution (10.0 L, 1 g / ml), cooled to 5°C and
stirred for at 5°C for 3 h. The reaction was filtered and the filter cake (product) was washed with
water (5.0 L) and dried under coarse vacuum. The dried product was dissolved in of ethyl acetate
(20.0 L), filtered through a plug of Celite®, washed with brine (5.0 L) and concentrated to yield
800 g of pure product 15 (75 % yield). 1H NMR (DMSOꢀd6, 400 MHz): δ 9.34 (s, 1H), 6.99 (d,
1H, J = 8.0 Hz), 6.67 (s, 1H), 6.66 (d, 1H, J = 8.0 Hz), 4.37 (s, 1H), 2.13 (s, 3H), 1.28 (s, 3H),
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1.27 (s, 3H), 1.17 (s, 3H), 0.70 (s, 3H); C NMR (DMSOꢀd6, 101 MHz): δ 214.6, 155.6, 131.2,
126.0, 115.4, 112.1, 77.8, 75.0, 67.6, 62.5, 27.7, 26.0, 25.1, 17.6, one carbon signal not observed;
HRMS m/e 276.13 [(M)+, calcd for C16H20O4 276.14].
4-(5-hydroxy-2-methyl-phenyl)-2,2,6,6-tetramethyl-tetrahydropyran-3,5-dione (3).
Procedure A
A solution of 1ꢀ(5ꢀhydroxyꢀ2ꢀmethylꢀphenyl)ꢀ5,5,7,7ꢀtetramethylꢀ2,6ꢀdioxaspiro[2.4]heptanꢀ4ꢀ
one (1.5 kg, 5.43 mol) in DCM (15.0 L) was cooled to 0°C. Conc. sulphuric acid (1.3 L, 24.48
mol, 4.5 eq.) was added over a period of 1.5 hr maintaining the reaction temperature below 5°C.
Thereafter the reaction mixture was stirred at 0ꢀ5°C for 15 min. The reaction progress was
monitored by HPLC. The reaction mixture was added to 13.0 L of ice cold water, stirred for 3 hr
and the solid was filtered. The filter cake was washed with water until neutral pH (~3 L) and
then dried at 50°C under high vacuum (water content below 1%) to yield pure product 3 (1050 g,
1
70% yield). H NMR (DMSOꢀd6, 400 MHz): δ 6.98 (d, 1H, J = 8.0 Hz), 6.60 (d, 1H, J = 8.0
13
Hz), 6.37 (s, 1H), 1.91 (s, 3H), 1.42 (s, 12H); C NMR (DMSOꢀd6, 101 MHz): δ 154.7, 132.6,
130.0, 127.4, 118.0, 114.1, 109.7, 74.9, 27.9, 18.0, four carbons not observed, HRMS m/e 276.13
[(M)+, calcd for C16H20O4 276.14].
Procedure B
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Amberlyst 15 Ion exchange resin (1 g) was added to a solution of 1ꢀ(5ꢀhydroxyꢀ2ꢀmethylꢀ
phenyl)ꢀ5,5,7,7ꢀtetramethylꢀ2,6ꢀdioxaspiro[2.4]heptanꢀ4ꢀone 15 (1 g, 3.6 mmol) in DCM (20
mL) at 25ꢀ30°C. The reaction mixture was stirred at this temperature for 22 hr. The conversion
monitored by HPLC. The reaction mass was filtered and the Amberlyst residue washed with
ethyl acetate (20 mL). The combined organic layer was concentrated under vacuum to afford the
desired product 3. (0.72 g, 72% yield). The analytical data of the product thus obtained was
identical in all respects to the one mentioned above in Procedure A.
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AUTHOR INFORMATION
Corresponding Author
*Telephone: +41 62 8660333. Eꢀmail: tomas.smejkal@syngenta.com.
Present Addresses
† (A.ꢀM.H.) Bristol Myers Squibb, External Manufacturing, Plaza 254, Blanchardstown
Corporate Park 2, Dublin 15, Ireland.
Author Contributions
‡(T.S. and V.G.) These authors contributed equally. The manuscript was written through
contributions of all authors. All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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We would like to thank our research, analytical and kilolab colleagues for their support to this
project in particular Mukul Lal and Damodar Karuturi.
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ABBREVIATIONS
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CDCl3, chloroformꢀd; CHCl3, chloroform; CTAB, cetyl trimethyl ammonium bromide; DMAP,
N,Nꢀdimethylꢀ4ꢀaminopyridine; DMSO, dimethylsulfoxide; eq, equivalents; EtMgBr, ethyl
magnesium bromide; EtMgCl, ethyl magnesium chloride; HCl, hydrochloric acid; HPLC, high
performance liquid chromatography; hr, hour; iꢀPrMgCl, isoꢀpropyl magnesium chloride; iꢀ
PrOH, isopropanol; MeMgBr, methyl magnesium bromide; MeMgCl, methyl magnesium
chloride; MeTHF, 2ꢀmethyl tetrahydrofurane; min, minute; MnCl2, manganese dichloride; nꢀ
BuLi, nꢀbutyl lithium; nꢀBuMgBr, nꢀbutyl magnesium bromide; NMR, nuclear magnetic
resonance; THF, tetrahydrofurane; TBME tertꢀbutyl methyl ether.
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