Preparation of Ethynylbenzene Derivatives from Substituted

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Preparation of Ethynylbenzene Derivatives from Substituted Benzaldehydes Jacek Martynow, Roger Hanselmann, Erin Duffy, and Ashoke Bhattacharjee Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 26 Mar 2019 Downloaded from http://pubs.acs.org on March 27, 2019

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Organic Process Research & Development

Preparation of Ethynylbenzene Derivatives from Substituted Benzaldehydes Jacek Martynow†, Roger Hanselmann‡, Erin Duffy, and Ashoke Bhattacharjee* Melinta Therapeutics Inc., 300 George Street, New Haven, CT 06511, USA.

ACS Paragon Plus Environment

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Organic Process Research & Development 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Table of Contents Graphic


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ABSTRACT: We have tested a number of synthetic methods for large scale synthesis of targeted substituted aromatic alkynes (S)- [4-(3-Chloro-5-ethynyl-4-fluoro-phenyl)-1-methyl-butyl]carbamic acid benzyl ester (1). This research resulted in an improved method for the Corey-Fuchs approach to alkyne synthesis from aldehydes. Importantly, we have shown that that the use of P(OCH3)3/CBr4 in toluene for the synthesis of dibromo-methylene intermediate (S)-{4-[3-Chloro5-(2,2-dibromo-vinyl)-4-fluoro-phenyl]-1-methyl-butyl}-carbamic acid benzyl ester (5) allows the synthesis of alkyne 1 under conditions that may be amenable for scaling-up. Since this method was developed, multiple batches of alkyne 1, each approaching 100 g in size have been prepared under process-friendly conditions, as well as multigram batches of other alkynes.

KEYWORDS: Benzaldehyde, Alkyne, Sonogashira, Corey-Fuchs, Ohira-Bestmann, Carbon tetrabromide, Trimethyl phosphite.

Introduction In connection with the preparation of key intermediates that were needed for the synthesis of novel pyrrolocytosine antibiotics1 on 100 g-scale and beyond, the existing medicinal chemistry synthetic routes (Scheme 1) necessitated a method for process-like synthesis of alkyne 1 (Figure 1). We investigated a number of approaches, and eventually found a satisfactory solution.


3


F

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Cl

(S)

NH Cbz 1

Figure 1. Structure of alkyne 1 targeted for process development. Result and Discussion The direct synthesis of alkynes (C, Scheme 1) from an aromatic halide A via a Sonogashira-type direct alkynylation reaction has been extensively utilized on a below one gram scale during the medicinal chemistry research effort (Scheme 1).1,2 Such halides or pseudo-halides A were synthetically accessible from commercially available precursors, including commercial halogenated anilines that could be further functionalized and then de-aminated to reveal the desired Sonogashira reaction substrates. However, a robust and efficient access to the targeted aryl alkynes was challenging due to the facile Glaser-Hay homocoupling of the products C. In the presence of Cu and/or Pd residues, despite the efforts to exclude oxygen, the Sonogashira reaction frequently afforded varying amounts of diyne by-products D. The facility of alkyne homocoupling under Sonogashira coupling conditions has been previously reported.3

Scheme 1. Small scale approaches to alkynes C.


4

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X1

H2N

1) NIS X2 2) NBS 3) Isoamyl nitrite 4) (S)

3

N H

X1

X2

X1

X

X2

PG

X1

X2

H

Cbz (S)

9-BBN in THF

NH Cbz

Ref. (1)

NH Cbz

X = Br, I, OTs, OTf

PG = TMS, CH3C(OH)CH3, -C(=O)OR

A X2

B

X1

NH Cbz

X1

C

X2

NH

CbzHN

D

Cbz

This difficulty was amplified on a multigram scale by the fact that applications based on TMSacetylene, propiolic acid and its esters, or the acetylene-ketone adducts (e.g. 2-methyl-3-butyn-2ol) as the alkyne component of the Sonogashira coupling require a subsequent deprotection of the initial adduct B.4 We observed that transition metal residues carried over from the coupling stage and were difficult to completely remove due to polar substituents – such as the carbamate group – present in B. During the deprotection stage and in spite of stringent exclusion of oxygen from the reaction media, we frequently observed varying amounts of the dimer by-products D. These adducts are known to form in the presence of copper salts.5 To remedy the alkyne homocoupling problem, we investigated the use of oxygen scavengers (such as ascorbic acid, BHT, or hydrogen admixture in the reaction atmosphere)6 in the various deprotection reactions but found that this approach was not effective in completely preventing alkyne homocoupling. Moreover, when we applied various copper-free conditions7 for Sonogashira couplings with protected alkynes such as TMS-acetylene, propiolic acid, or 2-methyl-3-butyn-2-ol, we isolated low yields (< 50%) of the desired coupled products, observed long reaction times (>14 h) and multiple by-products.8 We


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concluded that, due to the ease of the alkyne homocoupling, for the targeted synthesis of alkynes C on scale the tested variants of the Sonogashira coupling were not suitable. Another option that avoids the Sonogashira coupling-based access to the targeted alkynes would be the use acetyl-substituted aromatic intermediates, which can be converted to alkynes on the way of phosphazene base-induced elimination of enol nonaflate ester intermediates,9 however the high cost of the necessary reagents would prevent the application of this method on a larger scale. Scheme 2. Ohira-Bestmann vs Corey-Fuchs syntheses of alkynes C.

O

X1

X2

H

X X= Br, I, OTs, OMs, OTf B - Alkyl Suzuki reaction

Corey-Fuchs Approach X1

X2

LDA

H

Br

Br X1

X2

Yields 79-91% H

Cbz C

NH

Cbz F

NH

CBr4 P(OMe)3

O

Yields 56-94%

H

X1

X2

Ohira-Bestmann Approach O O MeO P CH3 MeO N2

X1

X2

H Column chromat. Yields 50-60 %

Cbz

NH

E

Cbz

NH

C

Alkyne C synthesis from an aldehyde precursor: Carbonyl compounds, especially aldehydes, are known to be convenient starting materials for the preparation of alkynes under conditions that do not involve transition metals and thus may avoid the problem of alkyne homocoupling.10 Of these, the Colvin rearrangement, and the SeyferthGilbert homologation,11 also in its improved Ohira-Bestmann variation,12 all utilize diazo compounds as key intermediates. Such intermediates, we felt, were rather risky to apply on scale, and were not commercially available. The most convenient preparation of diazo phosphonates


6

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unfortunately also requires the use of organic azides,13 which are similarly unsuitable for large scale-ups. Apart from the perceived risks associated with the use of azides and diazo reagents, the initial test experiments we ran according to the Ohira-Bestmann protocol on a gram scale of aldehydes E (Scheme 2) resulted in high levels of impurities, and the desired alkynes C were formed in 50-60% yield only. However, some of the available methods for alkyne synthesis from an aldehyde precursor do not involve diazo compounds – of these, the Corey-Fuchs method10,14 was quite appealing due to the use of readily attainable reagents, the potential for high yields, and especially due to the expected crystalline nature of the dibromomethylene intermediates F (Scheme 2) as a means for nonchromatographic removal of the impurities on the way to alkynes C.14,24a While we could not find literature reports of production-scale synthesis of alkynes using the Corey-Fuchs method, at least two previous literature reports mention the application of this method on a kilo-lab scale.15 We decided to further investigate this approach as a means to synthesize alkynes C. Regrettably, in the course of this project we were not successful in obtaining aldehydes E as solids. These compounds were synthesized in a B-alkyl Suzuki coupling reaction (Schemes 2 and 3) performed with a suitable B-alkylated 9-BBN derivative.16 We found that a preliminary conversion of the trialkyl borane to boronate complex by means of aqueous NaOH much facilitated the alkyl transfer stage.17 However, the thus obtained aldehydes E were contaminated with varying amounts of boron species that needed to be removed. On scale, the workup of reactions involving trialkyl boranes and/or their partially oxidized derivatives is a frequent concern18 - typically it requires oxidation of the boron compounds, which remain in the organic phase after reaction, to nonpyrophoric polar species that can be safely removed with the aqueous phase. We investigated nonchromatographic removal of boron-derived contaminants from aldehyde E solutions directly after


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the B-alkyl Suzuki coupling step, under a variety of conditions. The procedures we tested involved acid and base washes, treatment with absorbents containing MgSO4, silica gel and charcoal, a fluoride based method,19 and various oxidation methods, including sodium perborate,20 as well as urea-hydrogen peroxide (UHP), trimethylamine N-oxide, and H2O2-based approaches.21,18 However, these conditions were not effective due to either a rapid oxidation of the aldehydes to acids and/or due to incomplete removal of the 9-BBN-derived impurities. We also tested the practicality of the approaches based on aldehyde purification via a solid aldehyde-bisulfite adduct22 but in the case of our aldehydes, unfortunately, the effectiveness of precipitation of the bisulfite adduct(s) was low, under a variety of conditions. Therefore, we hoped that an oxidative work-up performed on the dibromomethylene intermediate F instead of the aldehyde E, might be a good option for the removal of boron-derived impurities, and this turned out to be the case. Development of the trimethyl phosphite/toluene approach for the synthesis of dibromomethylene derivatives from aldehydes: Triphenylphosphine

oxide

is

an

inconvenient

by-product

in

the

classic

Ramirez

dibromomethylenation23 such that it may require chromatographic purification of the product thus being a scale-up problem.4b Importantly, the more recent improvement introduced by Lautens,24a consisting in the application of triisopropyl phosphite in the Ramirez dibromomethylenation reaction, offers a good starting point for dibromomethylenation of the aldehydes E that could be adopted for preparation of alkynes C on scale. Table 1. Reaction of aldehyde 4 with CBr4- phosphite screena

entry

solvent

P(III) reagent/equiv

Temperature Time (h) (°C)

product purity

conclusions from HPLC monitoring


8

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(area %) 1

CH2Cl2

P(OiPr)3/2.0

0

0.5

83

rapid reaction, six minor impurities

2

toluene

P(OiPr)3/2.0

0

0.5

85

rapid reaction, four minor impurities

3

toluene

P(OiPr)3/2.0

20-25

0.5

86

rapid reaction, four minor impurities

4

CH2Cl2

P(OEt)3/2.2

0

1

79

five impurities

5

toluene

P(OEt)3/2.2

0

1

84

five impurities

6

CH2Cl2

P(OEt)2OH/2.2 20-25

1

18

very slow, impurities

7

toluene

P(OEt)2OH/2.2 20-25

1

11

very slow

8

CH2Cl2

P(OMe)3/2.1

0

1

77

4 imputities

9

toluene

P(OMe)3/2.1

0

1

12

1 impurity

10

toluene

P(OMe)3/2.1

20-25

1

50

2 ipurities

11

toluene

P(OMe)3/3.0

20-25

1

98

clean

aConditions:

Chromatographically pure 4 (200 mg scale) and CBr4 (1.5 equiv) dissolved under Ar in 1.5 mL solvent; brought to the desired temperature; P(III) reagent was dissolved in 1 mL solvent and added over 1 min; magnetic stirring.

However, we found out that triisopropyl phosphite is not, in fact, easily removed after the reaction. Although on a small-scale chromatography could be used,24 the harsher conditions required for triisopropyl phosphite hydrolysis (conc. HCl-AcOH, reflux overnight) during larger-scale


9


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applications were not compatible with our compounds, leading to decomposition. We tested a variety of alkyl phosphites in this reaction (Table 1) and were fortunate to discover that trimethyl phosphite/CBr4 in toluene, when used at the ratio of ca. 3 equivalents P(OMe)3, offered both a very fast and clean dibromomethylenetion reaction at room temperature, as well as ease of the hydrolysis step.25 Thus, the dibromomethylenation reaction can be conveniently run on scale, and the mixture after reaction can be cleanly worked up without a problem. Table 2. Reaction of aldehyde 4 with CBr4 and P(OEt)3 - solvent screena entry

solvent

time (h)

product purity conclusions (area %) from HPLC monitoring

1

acetonitrile

1

79

4 impurities

2

toluene

1

90

88.3% after additional 3 h at 0°C

3

dichloromethane

1

50

3 impurities (25, 12 and 12%)

4

N, N3 dimethylformamide

4

very slow

5

tetrahydrofuran

1

47

4 impurities

6

isopropyl acetate

1

71

4 impurities

a

Conditions: Chromatographically pure 4 (300 mg scale) and CBr4 (1.5 equiv) dissolved in 2 mL solvent; cooled to 0 °C under Ar, P(OEt)3 was dissolved in 1 mL solvent and added over 1 min; magnetic stirring. Another improvement, concomitant with the change of phosphite reagent, was made in the area of reaction solvent: we determined that toluene was the solvent of choice for trimethyl phosphitebased reactions (Tables 1 and 2). The use of toluene should also enhance the ‘greenness’ of largescale applications of the trimethyl phosphite/CBr4 approach.26


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Scheme 3. 100 g-scale synthesis of alkyne 1

1)

O

F

(S)

3

Cl

N H

Cbz

(1.1 eq) O

50% wt. Solution in toluene

F

Cl

H

9-BBN (1.3 equiv) in THF

H

I 2

2) 2N NaOH (2.2 equiv), Pd(PPh3)4 (1%), Toluene (2.4 vol), 50oC

(S)

NH Cbz

3) HCl, Water wash 4

Telescoped as a solution in toluene

F 1) CBr4 (1.5 equiv), P(OMe)3 (3eq), RT 2) 2N NaOH 3) H2O2 (5 equiv), 50oC 4) Na2SO3 and water wash 5) Solvent switch to IPA, crystallize 6) Filter (78 % over 2 steps)

Cl 1) LDA (4.5 equiv), THF (4.5 vol), -40oC

Br

Br

NH Cbz

1 2) Citric acid quench 3) Toluene extraction 4) MgSO4 (20%), SiO2 (20%), Darco (5%) slurry 5) Solvent exchange to IPA 6) Water 7) Filter (79 %)

5

According to the present method (Scheme 3), the aldehyde 4 formed as a result of the B-alkyl Suzuki reaction, is obtained after aqueous workup as a solution in toluene.27 The toluene solution of aldehyde 4 is telescoped to the dibromomethylenation reaction. After reaction completion, the organic layer containing compound 5 in toluene is quenched by addition to 2N NaOH (inverse addition is necessary due to the strong exotherm observed during the quench). After the NaOH quench, the organic phase is treated with H2O2-NaOH in order to oxidize the 9-BBN derived boron species. We found that this treatment is more effective when it includes a reaction segment run at 50-55 °C (ca. 2 h). In fact, the effectiveness of this approach can be monitored by following the changes visible in the aliphatic region of 1H-NMR spectra (DMSO-D6) of aliquots taken from the reaction mixture. After the H2O2 treatment, aqueous sulfite wash ensures that no detectable peroxides are present in the reaction mixture (KI-starch tests are performed at this stage). Following a solvent switch, the product 5 crystallizes from IPA-H2O in good purity, and the


11


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crystallization solvents are easily removed during the drying operation, affording compound 5 in 78% isolated yield, over two steps.

Final improvements in alkyne 1 synthesis from dibromomethylene precursor: For the alkyne formation reaction from dibromomethylene intermediate 5, we tested a number of basic conditions which are summarized in Table 3. Identifying the type of conditions that would be suitable for process scale was not trivial, as at least some stability is required at -20 °C to 0 °C in order to perform an aqueous work up. On the other hand, we also tested a number of higher temperature conditions, based on the report that Cs2CO3/DMSO at ca. 100 °C was effective for a similar transformation.28 These attempts gave the desired alkyne 1 in a low yield, with the bromoalkyne 6 (Figure 2) formed at varying levels, up to 70-90% (HPLC area%). We also observed that under these high temperature conditions, further debromination of bromoalkyne 6 to alkyne 1 was not easily accomplished, while increasing the temperature was associated with the formation of dimer D. However, the application of commercial 2.0 M LDA solution (Table 3, entries 1-3), at acceptably low temperatures (- 40 °C) resulted in a very clean transformation of the dibromoalkene 5 to alkyne 1. Importantly, stability tests indicated29 that the mixture had sufficient stability after completion of the reaction, allowing an aqueous work-up. Because of this satisfactory result we did not test other bases such as Grignard bases.10b Table 3. Reactions of dibromide 5 with bases, representative examplesa entry

base/equiv

solvent (v/w)

temperature (°C)

time (h)

results

1

LDA/4.5

THFb (5)

- 40

1

100% conversion, 98.0 % purity, stable for 2h at 20°C


12

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2

LDA/4.5

2-Me-THF (5)

-40

1

100% conversion, 96% purity, lack of stability at 20°C

3

LDA/4.5

Toluene (7)

-40

1

intractable gummy precipitate formed

4

KHMDS/4

THF (6)

-40

1

4% of 1, 92% of 6

0-5

0.5

decomposed

5

LHMDS/5

THF (6)

-40

1

11% of 1, 79% of 6

6

Cs2CO3/3

5% H2O/DMSO (7)

70-72

1

100% conversion, 9% dimer, mostly 6 formed

7

Cs2CO3/3

dry DMSO (12)

95

1

66% of 1, 23% of 6, 11% impurity. 70% of 1, 9% of 6, 21% impurity

2

8

Cs2CO3/3

2% H2O/DMSO (7)

95

3

80% of 1, 20% of 6, aqueous quench resulted in impurities, 40% of 1 and 32% 6

9

DBU/4

2-Me-THF (6)

0

2

22

1

50-55

1

20-25

1

0

0.5

60% conversion to 6. 92% conversion to 6. decomposed 70% of 6, decomposition

10

DBU/2

DMSO (5)

some decomposition 11

Ba (OH)2/3

DMF (6)

80-85

2

12% conversion, mostly to 6


13


12

K-OtBu/4

THF (10)

20-25

THF (10) + DMSO 20-25 (3) 0 K-OtBu/2.2

Page 14 of 28

1.5

1

1

THF (5) + DMPU (2)

precipitation, decomposition extensive decomposition 90% of 6, addition of 2 equiv base leads to decomposition 57% of 1, 41% of 6

13

K3PO4/2.5

3% H2O in DMSO 50-55 (5)

17

14

K3PO4/2.5

6% H2O in DMSO 68-70 (5)

24

96% of 1, 4% of 6

80-82

8

91% of 1, 3% of 6, 6% impurities 55% of 6 is formed. 10% of 1, 90% of 6

15

TBAF/2.2

DMSO (5)

20-25

3

TBAF/4

DMSO (4) +THF 20-25 (2)

3

a

Conditions: Crystalline 5 (200 mg scale) was dissolved under argon in the solvent indicated, the solution was brought to the desired temperature, and then treated with the base, magnetic stirring; the mixture was sampled for HPLC. After reaction the mixture was monitored for stability at -20 °C. b Commercial 2.0 M LDA solution in THF-PhEt-heptane was used (at least 80% THF).

For the crystallization of alkyne 1 we tested a number of solvent systems and, interestingly, the best type of crystallization conditions we found was very similar to the conditions that were earlier determined as optimal for the crystallization of dibromoalkene 5. After drying, the product 1 was obtained in a 79% yield and in good purity. This alkyne exhibited a very good stability upon storage, e.g. there have been no signs of decomposition during on-shelf storage of compound 1 at room temperature, over the course of one year.


14

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F

Cl

F

O CF3

F

Cl

F

Cl

Br

Cbz

NH

Cbz

6

NH

7

Boc

(S) NH

THP O Cbz

(R) NH

9

8

Figure 2. Structures of alkynes 6 - 9. Besides compound 1, congeners of this alkyne were also needed for the medicinal chemistry project in multigram quantities. Employing the present method, we also synthesized these other alkynes (Figure 2, compounds 7 -9). The syntheses were analogous with the described synthesis of compound 1, the route for compound 7 being very similar indeed, in that the product and the corresponding dibromomethylene intermediate both were crystalline. However, the Boc-amine 8 and the THP-protected compound 9, both required chromatography for purification of the final product.30, 31 Conclusion In summary, we have tested a number of synthetic methods for large scale synthesis of targeted substituted aromatic alkynes. This research resulted in an improved method for the Corey-Fuchs approach to alkyne synthesis from aldehydes. We have shown that that the use of trimethyl phopshite/CBr4 in toluene solution for the synthesis of intermediate 5 allows the synthesis of alkyne 1 under conditions that bear the promise to be amenable for a further scale-up. Since the method was developed, multiple batches of alkyne 1, each approaching 100 g in size have been prepared, as well as multigram batches of other alkynes. EXPERIMENTAL SECTION Analytical Methods


15


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A novel hundred-gram scale preparation of compounds 2 and 3 (ee > 98 %) (100 g – 200 g batches) was accomplished in-house and will be reported in due course. Melting points are uncorrected. 1Hand

13C-NMR

spectra were obtained on a Bruker Spectrospin 300 MHz instrument, and the

solvents are indicated. NMR J coupling constants are in Hertz. Inert atmosphere for reactions was provided by means of Airgas AR 300 industrial grade argon. LC MS analyses were obtained on a Shimadzu 2020 instrument. HPLC analyses were performed using a Waters Sunfire C18 column (150 x 2.1 mm, 3.5 µm silica); mobile phase A: 0.3% H3PO4 in water; mobile phase B: 0.3% H3PO4 in acetonitrile; flow rate: 0.3 ml/min; gradient: 0 min 5% B, 1 min 5% B, 27 min 100% B, 30 min 100% B, 30.5 min 5% B, 35 min 5% B; injections of 5-10 microliter were made; UV detection @ diode array (210-400 nm). HPLC samples typically were prepared by drawing 100 µL of reaction mixture and diluting the samples to 20 mL with acetonitrile or methanol, followed by filtration through a 0.45micron filter, when necessary. Combustion elemental analyses were carried out at Robertson Microlit Laboratories, NJ, USA. (S)-{4-[3-Chloro-5-(2,2-dibromo-vinyl)-4-fluoro-phenyl]-1-methyl-butyl}-carbamic acid benzyl ester (5). Boronylation: A 50% wt solution of (S)-(1-methyl-but-3-enyl)-carbamic acid benzyl ester (ee 99%; 119.3 g, 1.1 equiv) in toluene was added within 20 min to a 0.5 M solution of 9-BBN in THF (643 mL, 1.3 equiv) at 20-25 oC. The solution was stirred for 2 h at room temperature. The conversion of the olefin was monitored by 1H-NMR (DMSO-D6) of reaction mixture aliquots; a complete conversion was determined by the disappearance of the olefinic proton multiplet at 5.8 ppm. Solution of 2 and Pd (PPh3)4 in toluene:


16

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Compound 2 (70.35 g, 0.25 mol) was dissolved in toluene (169 mL, 2.4 vol) (the dissolution is endothermic). The solution was degassed and maintained under argon. To the clear solution, stirred under argon, was added Pd (PPh3)4 (2.84 g, 1 %) and the mixture was stirred for 15 min, until dissolved. B-Alkyl Suzuki reaction: 2N NaOH/H2O (271 mL, 2.2 equiv, degassed with argon) was added to the boronylation solution during 20 min, at 20-25 oC (CAUTION: the initial ca. 5% of NaOH addition is strongly exothermic), and the mixture was stirred for 20 min at 20-25 oC. Subsequently, the preformed solution of 2 and Pd (PPh3)4 in toluene was added within 20 min (NMT 30 oC) to the alkyl-boronate solution. The mixture was heated and stirred at 50-55 oC for 2 h (NMT 0.2% of 2 by HPLC), and then it was cooled to room temperature, and the aqueous layer was drained off (it was determined that at this stage the mixture can be left overnight at room temperature without any deterioration). The organic layer was washed with 5% Na (4)-EDTA/H2O (1 x 140 mL, 1 x 2 vol), 1N HCl/H2O (1 x 140 mL, 1 x 2 vol), and with water (2 x 140 mL, 2 x 2 vol). The solution was azeotropically dried at 45 oC /vac, and the volume was adjusted to 562 ml (8 vol) with toluene. Dibromomethylenation

reaction,

(S)-{4-[3-Chloro-5-(2,2-dibromo-vinyl)-4-fluoro-phenyl]-1-

methyl-butyl}-carbamic acid benzyl ester (5): CBr4 (123.0 g, 1.5 equiv) was added in a few portions (the dissolution is endothermic). P(OMe)3 (87.5 mL, 3.0 equiv) was added within 1 h at 15-25 oC and the mixture was stirred at 20-25 oC for 2h. During the addition and the subsequent stirring an exotherm occurred, and the yellow solution turned dark brown at ca. 20 min after P(OMe)3 addition. After the reaction was complete, the reaction mixture was added dropwise within 1 h to 2N NaOH/H2O (408 mL, 3.3 equiv) at 20-25


17


oC

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(initially exothermic), and then stirred at room temperature for 3h. It was determined that the

mixture can be left overnight at room temperature without any deterioration. The aqueous layer was removed, and 2N NaOH/H2O (408 mL, 3.3 equiv) was added to the organic solution. 30% H2O2/H2O (126.4 mL, 5 equiv) was added dropwise within 1h at 30-40 oC (CAUTION: after ca. 50% of H2O2 was added, off-gassing was observed, which was dosecontrolled). The mixture was stirred for an additional 2h at this temperature, followed by 2 h at 50-55 oC. The off-gassing continued for ca 1 h at 50-55 °C, and then it subsided. The mixture was cooled to room temperature and the aqueous layer was drained off. The organic layer was washed with 10% Na2SO3/H2O (210 mL, 3 vol; a KI-starch strip test of the organic layer was negative), and then with 10% NaCl/H2O (2 x 140 mL, 2 x 2 vol). The organic layer was solvent-switched to IPA at 45 oC /vacuum, and the volume was adjusted with IPA to 387 ml (5.5 vol.). It was determined that, at temperatures below 20 °C, the final IPA solution is super-saturated with respect to the dibromomethylene 5; however, the precipitation usually was not observed, and, if necessary, 5 can be re-dissolved in IPA at ca. 55 °C. The IPA solution was seeded (175 mg, 0.25% of 5) at 20-23 °C, and the crystallizing mixture was stirred overnight at room temperature. Water (210 mL, 3 vol) was added dropwise to the thick suspension over 2h, and the mixture was stirred at room temperature for an additional 4 h. The mixture was filtered, washed with IPA-water 5:3 (3 x 140 mL, 3 x 2 vol) and dried at 55-60 oC / 10 Torr to a constant mass, yielding 5 as light-beige crystals (103 g, 78% from aldehyde 2, purity 95.4% HPLC). Compound 5: mp 114-118°C; 1H-NMR (300 MHz, DMSO-D6): δ 7.71 (s, 1H), 7.44 (bd, 1H, J= 6.7), 7.33 (m, 6H), 7.13 (bd, 1H, J= 8.3), 5.00 (m, 2H), 3.54 (m, 1H), 2.58 (m, 2H), 1.54 (m, 2H), 1.37 (m, 2H), 1.03 (d, 3H, J= 6.5). MS (ESI, M+1 m/e 531.8, 533.9 and 535.9). The major impurity (HPLC at RRT 0.95; 1.8 area%) in 5 was


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determined to be the bromoalkyne 6 (MS, ESI, M+1 m/e 452.0 and 454.0) which is an intermediate in the next step and thus has no negative impact on the overall yield. (S)- [4-(3-Chloro-5-ethynyl-4-fluoro-phenyl)-1-methyl-butyl]-carbamic acid benzyl ester (1): Compound 5 (113.7 g, 213.06 mmol) was dissolved in THF (515 mL, 4.5 vol). The solution was cooled under argon to (-39 ° to -43 °C) and then 2.0 M LDA solution (479.4 mL, 4.5 eq, Aldrich #361798, 2.0M in THF-heptane-PhEt) was added within 70 min. The mixture was stirred at (- 39 ° to - 43 °C) for 1 h (HPLC: 5 < 0.1%). Afterwards, 1.5 M citric acid (285 mL, 2.0 equiv) was added dropwise within 45 min, while maintaining the temperature at - 32 ° to - 40 °C. CAUTION: initially a strong exotherm develops. Good mechanical stirring is necessary at this stage due to the abundant precipitation. Second portion of 1.5 M citric acid/H2O (285 mL, 2.0 equiv) was added while the mixture was being warmed up to 15-20 °C during 30 min, and then the mixture was stirred for 1 h, at room temperature. The mixture was extracted with toluene (570 mL, 5 vol) and the organic phase was washed once with a mixture of 5% aqueous citric acid-brine (720 mL, 6.3 vol; made from 685 mL 5% citric acid and 35 ml sat. brine), and twice with 5% brine (600 mL, 5.3 vol). The organic phase was azeotropically dried with toluene under vacuum, and set to a volume of 400 mL (3.5 vol) with toluene. The solution was treated with a mixture of Si-gel (230-400 mesh, 22.8 g, 20 wt %), anhydrous MgSO4 powder (22.8 g, 20 wt %) and charcoal DARCO G-60 (5.7 g, 5 wt %), and stirred for 14 h at room temperature,32 and then it was filtered through Celite; (3 x 115 mL, 3 x 1 vol) toluene was used for washing. The toluene solutions were combined and solvent-exchanged to IPA; the volume was adjusted to 555 mL (4.9 vol) with IPA. This IPA solution was added within 2 h 30 min to a mixture of water (796 mL, 7 vol), IPA (160 mL, 1.4 vol) and seeds (50 mg, 0.05 wt %) at room temperature. The suspension was gently stirred


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overnight, filtered, washed with IPA-H2O (4:5; 2 x 160 mL, 2x 1.4 vol), and dried at 55-60 °C / 10 Torr, yielding compound 1 as a light tan-colored solid (62.75 g, 79%, purity 98.5 area% by HPLC); mp 121-123 °C; 1H-NMR (300 MHz, DMSO-D6): δ 7.48 (dd, 1H, J= 6.9, 1.8), 7.32 (m, 6H), 7.14 (bd, 1H, J= 8.1), 5.00 (bs, 2H), 4.64 (s, 1H), 3.54 (m, 1H), 2.51 (m, 2H), 1.52 (m, 2H), 1.40 (m, 2H), 1.03 (d, 1H, J= 6.6) ; 13C-NMR (75 MHz, CDCl3): an assigned spectrum is provided in the SI section; MS (ESI) M+1 m/e 424; for C21H21ClFNO2 calc C 67.47, H 5.66, Cl 9.48, F 5.08 N 3.75; found: C 67.00, H 5.77, Cl 9.40, F 5.18, N 3.68. Using the same synthetic approach, the following alkynes were also prepared: (S)- [4-(3-Ethynyl-4-fluoro-5-trifluoromethoxy-phenyl)-1-methyl-butyl]-carbamic acid benzyl ester (7). Step 1 (dibromomethylenation of aldehyde) gave 76.8 g (56% isolated yield, HPLC purity 98.8 area %) of the corresponding dibromo intermediate. Step 2 (reaction with LDA) gave the corresponding alkyne 7 (50.6 g, 91% yield; HPLC purity 99.8 area %) as an off-white solid; mp 116-120 °C; 1H-NMR (300 MHz, DMSO-D6): δ 7.45 (m, 2H), 7.33 (m, 5H), 7.14 (bd, 1H, J= 8.1), 5.02 (bs, 2H), 4.69 (s, 1H), 3.56 (m, 1H), 2.60 (m, 2H), 1.56 (m, 2H), 1.42 (m, 2H), 1.04 (d, 3H, J= 6.6) ; 13C-NMR (75 MHz, CDCl3): an assigned 13C-NMR spectrum is provided in the SI section; MS (ESI) M+1 m/e 374; for C22H21NO3F4 calc C 62.41, H 5.00, F 17.95 N 3.31; found: C 62.28, H 5.10, F 17.93, N 3.28. (S)- [4-(3-Chloro-5-ethynyl-4-fluoro-phenyl)-1-methyl-butyl]-carbamic acid tert-butyl ester (8): Step 1 (dibromomethylenation of aldehyde) gave, after chromatography on silica gel (17 % ethyl acetate/heptane) the corresponding dibromomethylene intermediate (11.3 g, 62 % isolated yield; HPLC purity 95.7 area %). Step 2 (reaction with LDA) gave, after chromatography on silica gel (15 % ethyl acetate/heptane), the corresponding alkyne 8 (6.1 g, 79 % yield; HPLC purity 98.9 area %) as a semisolid, which slowly solidified; mp 40-43 ° C; 1H-NMR (300 MHz, CDCl3): δ


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7.20 (m, 2H), 4.30 (bs, 1H), 3.69 (m, 1H), 3.32 (s, 1H), 2.53 (m, 2H), 1.45 (bs, 9H), 1.42 (m, 2H), 1.11 (d, 3H, J=6.6 Hz) ; 13C-NMR (75 MHz, CDCl3): an assigned 13C-NMR spectrum is provided in the SI section; for C18H23NO2FCl calc C 63.62, H 6.82, Cl 10.43, F 5.59 N 4.12; found: C 63.55, H 6.81, Cl 10.43, F 5.68, N 4.05. (R)-[4-(3-Chloro-5-ethynyl-4-fluoro-phenyl)-1-(tetrahydro-pyran-2-yloxymethyl)-butyl]carbamic acid benzyl ester (9): Step 1 (dibromomethylenation of aldehyde) gave, after chromatography on silica gel (22 % ethyl acetate/heptane) the corresponding dibromomethylene intermediate (26.0 g, 94 % isolated yield; HPLC purity 98.7 area %). Step 2 (reaction with LDA) gave, after chromatography on silica gel (18% ethyl acetate/heptane), the corresponding alkyne 9 (15.7 g, 81% yield; HPLC purity 99.1 area %) as a gummy solid; 1H-NMR (300 MHz, CDCl3): δ 7.34 (m, 5H), 7.18 (m, 2H), 5.10 (m, 2H), 5.08 (m, 1H), 4.53 (m, 1H), 3.75 (m, 3H), 3.49 (m, 2H), 3.33 (s, 1H), 2.56 (m, 2H), 1.25-1.95 (bm, 8H); 13C-NMR (75 MHz, CDCl3): an assigned 13CNMR spectrum is provided in the SI section; MS (ESI) M+23 (Na) m/e 496.4.

ASSOCIATED CONTENT Supporting Information is available free of charge on the ACS publication website at DOI: The following files are available free of charge. 13C-NMR

assignment of alkyne 1, 7, 8 & 9. (file type, i.e., PDF)

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] ORCIDID


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Ashoke Bhattacharjee: 0000-0002-0609-7830 Present Addresses †(JM) Evonik corporation, Lafayette, IN. ‡ (RH) X4 Pharmaceuticals, Cambridge, MA. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT We thank our colleagues at Melinta Therapeutics for executing and repeating some of these works. REFERENCES 1. Duffy, E. M.; Bhattacharjee, A. Antimicrobial Compounds and Methods of making and using the same. WO 2012173689 A2 20121220, 2012. 2. General reviews of the Sonogashira coupling: (a) Magano, J.; Dunetz, J. R. Large-Scale Applications of Transition Metal-Catalyzed Couplings for the Synthesis of Pharmaceuticals, Chem. Rev. 2011, 111, 2177-2250; Chinchilla, R.; Nájera, C. The Sonogashira Reaction: A Booming Methodology in Synthetic Organic Chemistry, Chem. Rev. 2007, 107, 874-922. (b) Negishi, E.-I.; Anastasia, L. Palladium-Catalyzed Alkynylation, Chem. Rev. 2003, 103, 1979-2018. 3. (a) Pu, X.-T.; Li, H.-B.; Colacot, T. J. Heck Alkynylation (Copper-Free Sonogashira Coupling) of Aryl and Heteroaryl Chlorides, using Pd Complexes of t-Bu2(p-NMe2C6H4) P: Understanding the Structure-Activity Relationships and Copper Effects, J. Org. Chem. 2013, 78, 568-581. (b) Campbell, I. D.; Eglinton, G. Diphenyldiacetylene [Butadiyne, diphenyl-], Org. Syntheses 1965, 45, 39-42. (c) Vilhelmsen, M. H.; Jensen, J.; Tortzen, C.; Nielsen, M. B. The Glaser-Hay reaction: optimization and scope based on 13C NMR


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kinetics experiments, Eur. J. Org. Chem. 2013, 701-711. (d) Ye, C.; Xiao, J.-C.; Twamley, B.; LaLonde, A. D.; Norton, M. G.; Shreeve, J. M. Basic Ionic Liquids: Facile Access for Carbon-Carbon Bond Formation Reactions and Ready Access to Palladium Nanoparticles, Eur. J. Org. Chem. 2007, 5095-5100. 4. (a) Nishihara, Y.; Ikegashira, K.; Hirabayashi, K.; Ando, J-I.; Mori, A.; Hiyama, T. Coupling Reactions of Alkynylsilanes Mediated by a Cu(I) Salt: Novel Syntheses of Conjugate Diynes and Disubstituted Ethynes, J. Org. Chem. 2000, 65, 1780-1787. (b) Königsberger, K.; Chen, G.-P.; Wu, R. R.; Girgis, M. J.; Prasad, K.; Repič, O.; Blacklock, T. J. A Practical Synthesis of 6-[2-(2,5-Dimethoxyphenyl) ethyl]-4ethylquinazoline and the Art of Removing Palladium from the Products of Pd-Catalyzed Reactions, Org. Process Res. Dev. 2003, 7, 733-742. (c) Li, J.; Huang, P. A rapid and efficient synthetic route to terminal arylacetylenes by tetrabutylammonium hydroxideand methanol-catalyzed cleavage of 4-aryl-2-methyl-3-butyn-2-ols, Beilstein J. Org. Chem. 2011, 7, 426-431. (d) Anastasia, L.; Negishi, E.-I. Highly Satisfactory Procedures for the Pd-Catalyzed Cross Coupling of Aryl electrophiles with in Situ Generated Alkynylzinc Derivatives, Org. Lett. 2001, 3, 3111-3113. (e) Tartaggia, S.; De Lucchi, O.; Gooßen, L. J. Practical Synthesis of Unsymmetrical diarylacetylenes from Propiolic Acid and two Different Bromides, Eur. J. Org. Chem. 2012, 7, 1431-1438. 5. Niu, X.; Li, C.; Li, J.; Jia, X. Importance of bases on the copper-catalyzed oxidative homocoupling of terminal alkynes to 1,4-disubstituted 1,3-diynes, Tetrahedron Lett. 2012, 53, 5559-5561. 6. (a) Liu, F.; Negishi, E.-I. Efficient and Stereoselective Synthesis of Freelingyne via PdCatalyzed Cross Coupling and Lactonization, J. Org. Chem. 1997, 62, 8591-8594. (b) Elangovan, A.; Wang, Y.-H.; Ho, T.-I. Sonogashira Coupling Reaction with Diminished Homocoupling, Org. Lett. 2003, 5, 1841-1844. 7. (a) Finke, A. D.; Elleby, E. C.; Boyd, M. J.; Weissman, H.; Moore, J. S. Zinc ChloridePromoted Aryl Bromide-Alkyne Cross-Coupling Reactions at Room Temperature, J. Org. Chem. 2009, 74, 8897-8900. (b) Shirakawa, E.; Kitabata, T.; Otsuka, H.;


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Tsuchimoto, T. A simple catalyst system for the palladium-catalyzed coupling of aryl halides with terminal alkynes, Tetrahedron 2005, 61, 9878-9885. (c) Soheili, A.; Albaneze-Walker, J.; Murry, J. A.; Dormer, P. G.; Hughes, D. L. Efficient and General Protocol for the Copper-Free Sonogashira Coupling of Aryl Bromides at Room Temperature, Org. Lett. 2003, 5, 4191-4194. 8. In our synthetic route, alkynes C were required as starting materials for a subsequent Sonogashira protocol. Forewarned by the observed facility of the undesired Glaser-Hay homocouplings, we also investigated a direct application of the initial, still protected, Sonogashira products B (Scheme 1) in a subsequent Sonogashira coupling-cyclization step where the deprotection of the protected alkynes occurs in situ.1,8a, b However, we found that such an approach was associated with decomposition of the starting materials and with very low isolated yields. (a) Novák, Z.; Nemes, P.; Kotschy, A. Tandem Sonogashira Coupling: An Efficient Tool for the Synthesis of Diarylkynes, Org. Lett. 2004, 6, 4917-4920. (b) Iso, Y.; Kozikowski, A. P. Synthesis of 4-Arylethyl-2methyloxazole Derivatives as mGluR5 Antagonists for the Use in the treatment of Drug Abuse, Synthesis 2006, 243-246. (c) Bellina, F.; Lessi, M. Mild Pd/Cu-Catalyzed SilaSonogashira Coupling of (Hetero)aryl Bromides with (Hetero)aryethynylsilanes under PTC Conditions, Synlett 2012, 23, 773-777. 9. Lyapkalo, I. M.; Vogel, M. A. K.; Boltukhina, E. V.; Vavŕík, J. A General One-Step Synthesis of Alkynes from Enolisable Carbonyl compounds, Synlett 2009, 558-561. 10. (a) Habrant, D.; Rauhala, V.; Koskinen, A. M. P. Conversion of carbonyl compounds to alkynes: general overview and recent developments, Chem. Soc. Rev. 2010, 39, 20072017. (b) Benfodda, Z.; Bénimélis, D.; Reginato, G.; Meffre, P. Ethynylglycine Synthon, a Useful Precursor for the Synthesis of Biologically Active Compounds: An Update-Part 1: Preparations of Ethynylglycine Synthon, Amino Acids 2015, 47, 271-279. 11. (a) Seyferth, D.; Marmor, R. S.; Hilbert, P. Reactions of dimethylphosphono-substituted diazoalkanes. (MeO)2P(O)CR transfer to olefins and 1,3-dipolar additions of (MeO)2P(O)C(N2) R, J. Org. Chem. 1971, 36, 1379-1386. (b) Gilbert, J. C.; Weerasooriya, U. Diazoethenes: their attempted synthesis from aldehydes and aromatic


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ketones by way of the Horner-Emmons modification of the Wittig reaction. A facile synthesis of alkynes, J. Org. Chem. 1982, 47, 1837-1845. 12. Roth, G. J.; Liepold, B.; Müller, S. G.; Bestmann, H. J. Further Improvements of the Synthesis of Alkynes from Aldehydes, Synthesis 2004, 59-62. 13. Brown, D. G.; Velthuisen, E. J.; Commerford, J. R.; Brisbois, R. G.; Hoye, T. R. A Convenient Synthesis of Dimethyl (Diazomethyl)phosphonate (Seyferth/Gilbert Reagent), J. Org. Chem. 1996, 61, 2540-2541. 14. (a) Corey, E. J.; Fuchs, P. L. A synthetic method for formyl to ethynyl conversion, Tetrahedron Lett. 1972, 13, 3769-3772. (b) Wolf, J.; Eberspächer, I.; Groth, U.; Huhn, T. Synthesis and Photoswitching Studies of OPE-Embedded Difurylperfluorocyclopentenes, J. Org. Chem. 2013, 78, 8366-8375. 15. (a) Thomas, A. V.; Patel, H. H.; Reif, L. A.; Chemburkar, S. R.; Sawick, D. P.; Shelat, B.; Balmer, M. K.; Patel, R. R. Fenleuton: Development of a Manufacturing Process, Org. Process. Res. Dev. 1997, 1, 294-299. (b) Skoda, E. M.; Davis, G. C.; Wipf, P. Allylic Amines as Key Building Blocks in the Synthesis of (E)-Alkene Peptide Isosteres, Org. Process. Res. Dev. 2012, 16, 26-34. 16. (a) Al-Hellani, R., Schlüter, A.D. On the Synthesis and Selective Deprotection of Lowgeneration Dendrons with Orthogonally Protected Peripheral Amine Groups and a Possible Impact of the Deprotection Conditions on the Stability of Dendronized Polymers’ Skeletons, Helvetica Chim. Acta 2006, 89, 2745-2763. (b) Chemler, S.R.; Trauner, D.; Danishefsky, S. J. The B-Alkyl Suzuki-Miyaura Cross-Coupling Reaction: Development, Mechanistic Study, and Applications in Natural Product synthesis, Angew. Chem., Int. Ed. 2001, 40, 4544-4568. 17. Miyaura, N. Organoboron Compounds. In Topics in Current Chemistry, Vol. 219; Springer Verlag; Berlin Heidelberg, 2002; pp. 11-59. 18. Atkins, W. J.; Burkhardt, E. R.; Matos, K. Safe Handling of Boranes at Scale, Org. Process Res. Dev. 2006, 10, 1292-1295.


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19. Bio, M. M.; Hansen, K. B.; Gipson, J. A Practical, Efficient Synthesis of 1,1-Dioxohexahydro-1λ6-thiopyran-4-carbaldehyde, Org. Process Res. Dev. 2008, 12, 892-895. 20. Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M. Sodium Perborate: a mild and convenient reagent for efficiently oxidizing organoboranes, J. Org. Chem. 1989, 54, 5930-5933. 21. Astbury, G. R. Safe Scale-Up of Oxidation by Hydrogen Peroxide in Flammable Solvents, Org. Process Res. Dev. 2002, 6, 893-895. 22. (a) Pandit, C. R.; Mani, N. S. Expedient Reductive Amination of Aldehyde Bisulfite Adducts, Synthesis 2009, 4032-4036. (b) Frederick, M. O.; Frank, S. A.; Vicenzi, J. T.; LeTourneau, M. E.; Berglund, K. D.; Edward, A. W.; Alt, C. A. Development of a Hydrogenative Reductive Amination for the Synthesis of Evacetrapib: Unexpected Benefits of water, Org. Process Res. Dev. 2014, 18, 546-551. 23. (a) Desai, N. B.; McKelvie, N. Ramirez, F.; A New Synthesis of 1,1-Dibromoolefins via Phosphine-Dibromomethylenes. The reaction of Triphenylphosphine with Carbon Tetrabromide, J. Am. Chem. Soc. 1962, 84, 1745-1747. (b) Michel, P.; Gennet, D.; Rassat, A. A one-pot procedure for the synthesis of alkynes and bromoalkynes from aldehydes, Tetrahedron Lett. 1999, 40, 8575-8578. 24. (a) Fang, Y.-Q.; Lifchits, O.; Lautens, M. Horner-Wadsworth-Emmons modification for Ramirez gem-dibromoolefination of aldehydes and ketones using P(O-iPr)3, Synlett 2008, 413-417. (b) For a recent application of HCBr3/TiCl4/Mg in the dibromomethylanation of aldehydes and ketones, see: Bhorge, Y. R.; Chang, C.-T.; Chang, S.-H.; Yan, T.-H. CHBr3/TiCl4/Mg as an Unusual Nucleophilic CBr2 Carbenoid: Effective and Chemoselective Dibromomethylenation of Aldehyde and Ketones, Eur. J. Org. Chem. 2012, 4805-4810. 25. (a) Westheimer, F. H.; Huang, S.; Covitz, F. Rates and mechanism of hydrolysis of esters of phosphorous acid, J. Am. Chem. Soc. 1988, 110, 181-185; (b) McIntyre, S. K.; Alam, T. M. 17O NMR investigation of phosphite hydrolysis mechanism, Magn. Reson. Chem. 2007, 45, 1022-1026; (c) For a discussion of alkyl phosphite applications in the Arbuzov


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reaction of alkynes, see: Miller, S. I.; Fujii, A. Nucleophilic substitution at acetylenic carbon. Kinetics and mechanism of the Arbuzov reaction of substituted phenylbromo-and phenylchloroacetylenes with triethyl phosphite, J. Am. Chem. Soc. 1971, 93, 3694-3700. 26. Henderson, R. K.; Jiménez-González, C.; Constable, D. J. C.; Alston, S. R.; Inglis, G. G. A.; Fisher, G.; Sherwood, J.; Binks, S. P.; Curzons, A. D. Expanding GSK’s solvent selection guide – embedding sustainability into solvent selection starting at medicinal chemistry, Green Chem. 2011, 13, 854. 27. Before any further scale up, we tested three batches of this toluene solution for ability to self-ignite in the presence of air, on a gram scale, by evaporating them and leaving the oily residue at room temperature, open to air, for days. No signs of pyrophoric behavior were observed. 28. Zhao, M.; Kuang, C.; Yang, Q.; Cheng, X. Cs2CO3– mediated synthesis of terminal alkynes from 1,1-dibromo-1-alkenes, Tetrahedron Lett. 2011, 52, 992-994. 29. After IPC pass, the solution is stable for at least 4 h at -40 ° C. Stability tests, run at -20 ° C on the reaction mixture that was not quenched, gave ca. 10 % decomposition after 1 h. 30. The 13 C-NMR assignments of this small family of structurally-related alkynes were facilitated by the available F-C coupling data for fluorinated aromatic compounds, see: Lichter, R. L.; Wasylishen, R. E. Fluoropyridines. Carbon-13 chemical shifts and carbonfluorine coupling constants, J. Am. Chem. Soc. 1975, 97, 1808-1813, and references cited therein. 31. We observed that, in some cases, during silica gel chromatography the corresponding dibromomethylene intermediates F were obtained in yields consistently lower by ca. 20% than in the case of non-chromatographic isolation. A literature report24a revealed that the stability of dibromomethylene compounds on silica gel can be problematic. We suggest that chromatography of dibromomethylene compounds F should probably be avoided, and that the purification of such compounds on the way of crystallization is therefore preferred.


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32. The treatment with charcoal-silica gel-MgSO4 was very effective in removing the tarry, 9-BBN-derived residues that, if not removed, would form speckles amid the crystals of alkyne 1.


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Preparation of Ethynylbenzene Derivatives from Substituted

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