XX TrxR Thioredoxin reductase
I. Introduction
4. Results and Discussion: Synthesis of Target Benzenesulfonates
4.3. Changing Directions: Pathway B as an Alternative Route
123
Figure 4.6. A portion of the 1H NMR spectrum of the flavanone product showing the characteristic aliphatic proton signals with both germinal and vicinal coupling.
124
Scheme 4.7. Synthesis of 111 through Pathway B.
O O
O
O
O O
OH O O
Br
+ +
60 61 62 99
111
As these benzylated chalcones could now be synthesized easily, addition of the sulfonyl chloride moiety to form 62a (Scheme 4.8) was attempted with chlorosulfonic acid as described by Talley, et al,722 in the synthesis of valdecoxib, and Silva, et al.723 Yields of this reaction were disappointing, with a 30% mass recovery obtained after workup, and following NMR analysis of the disappointingly complex mixture it was determined that, while the sulfonyl chloride was attached to the molecule, it was located at the 4-position of the acetophenone ring (62b), rather than on the benzyl ring as desired, a result which cannot be explained in terms of the relative directing effects of the substituents on the two aromatic rings.
Scheme 4.8. Addition of sulfonyl chloride to 62.
X
O O
S O
O Cl
O O
O O
S O Cl O
62a 62 62b
125
As Pathway B appeared more appropriate for the synthesis of these compounds, alternate compounds were sought which could be manipulated to yield the final compounds with substitutions at the correct positions. Likely candidates were identified in 4-(bromomethyl)benzenesulfonyl chloride 112 and the significantly more expensive 4-(bromomethyl)benzenesulfonamide 113160 (Figure 4.7), as a replacement for benzyl bromide, as the sulfonyl moiety was already in place.
O S O Cl
Br Br
S O
O NH2
112 113
Figure 4.7. 2D structures of 4-(bromomethyl)benzenesulfonyl chloride 112 and 4-(bromomethyl)benzenesulfonamide 113.
However, initial reactions between the 2’-hydroxyacetophenones and 112 yielded a tosylated acetophenone compound, rather than the desired ether (Scheme 4.9). As 112 is a tosyl chloride derivative, this reaction was not unexpected, and it was therefore determined that the sulfonyl chloride needed to be protected in order to form the ether bond between the bromide and the hydroxyl group.
A search of the literature yielded large amounts of information on the use of sulfonyl chlorides as protecting groups, but surprisingly little information is available on the protection of the sulfonyl groups themselves.724
126
Scheme 4.9. General scheme for the formation of tosylated 2’-hydroxyacetophenones.
O S O Cl O Br
O
S O
O Cl
O
OH
O
O S
O O
Br
X
+R R R
Rather than focus on one protecting group for both sulfonate and sulfonamide compounds, both nitrogen- and oxygen-based protecting groups were tested in order to simplify the synthetic route. A protocol for the conversion of the sulfonyl chloride to a sulfonamide using aqueous ammonia had previously been established (Scheme 4.4), and this methodology proved successful with 112, however, while easy to synthesize, 113 proved too unstable under the subsequent reaction conditions. As attempts to protect the sulfonamide after it had been formed using amine protecting groups such as Boc and ethyl chloroformate were unsuccessful, primary and secondary amines were explored as alternatives. Initial testing of various amines and alcohols were carried out using a variety of conditions, with 65 selected as a simple test compound. This evaluation consisted of both protection703,725-727
and deprotection728-731 steps in order to identify those groups which could be easily added and removed without affecting the remainder of the molecule (Table 4.5).
Scheme 4.10. Formation of protected sulfonyl chlorides and subsequent deprotection.
S
O O
Cl
S
O O
PG
S
O O
X
X = OH, NH2
127
Table 4.5. Protection and Deprotection of 65.
Entry Amine/Alcohol Protecting
group Compound Protection Yield /%a
Deprotection Yield /%a
1 Diethylamine725 -N(Et)2 114732 90b 0h
2 Diisopropylamine725 -N(iPr)2 115733 5b,c -
3 Dibenzylamine725 -NBz2 116734 8b,c -
4 Acetamide725 -NHC(=O)CH3 117 15b,d -
5 Succinamide725 -NSucc 118735 25b,d -
6 Phthalamide725 -NPhth 119725 86b 81i
7 Ethanol726 -OEt 120736 90e 93f,j
8 tButanol726 -OtBu - 0e,f -
9 iPropanol726 -OiPr - 0e,f -
10 Phenol727 -OPh 121737 75g 0h
11 p-Nitrophenol727 -OPhNO2 122 86c,g 0h
a1H NMR yield b65, amine, KOH (1.1 eq), MeCN, rt, 2 h cnot characterized duncharacterized products (NMR) e65, KOH (1.1 eq), alcohol, rt, 2 h fpotassium salt isolated g65, KOH (1.1 eq), alcohol, THF/H2O (20:1), 0 ˚C, 2 h. hmultiple deprotection methods attempted. ihydrazine hydrate (80%), reflux, 30min jKOH (1 eq), EtOH/H2O (1:2) reflux, 1h.
Based on these test reactions, phthalamide was selected as a suitable amine protecting group, and ethanol as the acid protecting group. The ethoxy group could be cleaved using a base726 and the phthalamide group could be easily cleaved under Gabriel-type conditions by heating with hydrazine hydrate to reflux. 728-729 Protection of 112 proceeded smoothly, yielding the corresponding protected (bromo-methyl)tosylates 123738 and 124739 (Figure 4.8) in good to very good yields (Table 4.6).
128
Br
S
O O
OEt
Br
S
O O
O N O
123 124
Figure 4.8. 2D structures of 123 and 124
Table 4.6. Yields for the formation of protected (bromomethyl)tosylates.
Entry Compound Yield/%
1 123 88a
2 124 84b
a112, KOH (1.1 eq), EtOH, rt, 2 h b112, phthalimide, KOH (1.1 eq), MeCN, 0˚C, 1 h
Formation of the ether bond between 60 and 123 (Scheme 4.11) initially proved challenging as 123 is sparingly soluble in acetonitrile. However, there is sufficient 123 present in solution at any given time to allow the reaction to proceed, and to provide very good yields of the ether product after 24 hours.
Interestingly, the isolated product was not the ether sulfonate with an ethoxy- protecting group as expected; rather the potassium salt of 125 was obtained as a precipitate.
129
Scheme 4.11. Synthesis of benzenesulfonate 125.
OH O
Br
S
O O
OEt
O
O
S O
O X +
X = OEt, O- K+
60 123 125
As there was no evidence of sulfonate ester formation between two molecules of 123, the hypothesis is that 123 is the reactive species, and hydrolysis to the salt follows the reaction with 60. This hypothesis is supported by the unsuccessful reactions of the salt form of 112 with 60. Attempts to prevent the removal of the ethoxy group were unsuccessful, as when one equivalent of potassium carbonate was used, the ether reaction proceeded to ca. 50% and no further, and additional attempts to convert the potassium salt back to the ether after hydrolysis were unsuccessful. Organic bases such as DBU and DABCO were also tested; however these did not yield as clean a conversion as the potassium carbonate/acetonitrile conditions. A test condensation reaction of 125 with benzaldehyde 63 showed the presence of the salt did not affect the condensation reaction, and as such, further ether reactions made use of the potassium carbonate/acetonitrile conditions as the final products could be isolated cleanly and in good yields by filtration (Table 4.7). While fluoro- and chloro-substitutions at the 4-position of the acetophenone ring were well tolerated (Table 4.7, entries 2 and 3), the 5-substituted 2’-hydroxyacetophenones 128, 87 and 93 were remarkably unstable under these conditions (Table 4.7, entries 4-6), and even use of the mild potassium carbonate/acetone conditions696 resulted in rapid discolouration of the reaction medium and decomposition of the substituted acetophenone components.
130
Table 4.7. Yields for the formation of various 4-[2-(2-acetylphenyl)ethyl]benzenesulfonates.
Entry 2’-Hydroxyacetophenone Product Yield /%
1 H (60) 125 83
2 4-F (76) 126 79
3 4-Cl (82) 127 72
4 5-F (128) 129 15a
5 5-Cl (87) 130 12a
6 5-Br (93) 131 9a
Conditions: 123 (1 mmol), appropriate 2’-hydroxyacetophenone (1mmol), K2CO3 (2 mmol, 2 eq), MeCN, reflux, 24 h.
aNMR yield, multiple uncharacterized products.
Compound 124 on the other hand, proved to be too insoluble to be useful. It is remarkably insoluble in almost all organic solvents, apart from DMF and DMSO, and even the ether reactions carried out in DMF were low yielding. At this point, it was decided that compounds 125-127 would be carried forward into the condensation reactions, and the sulfonate converted into the sulfonamide through the sulfonyl chloride at a later stage if needed.
The condensation reactions of 125, 126 and 127 with the various benzaldehydes (Scheme 4.12) to yield the thirty compounds identified previously made use of a modified version of the procedure used for synthesis of the chalcones (Table 4.8). Reactions using 125 and 126 (Table 4.8, entries 1-24) proceeded cleanly under the conditions employed, with yields for reactions using 126 slightly lower than those obtained for compound 125. Reactions with 127 did not proceed as well as hoped under the conditions used for 125 and 126, with yields ranging from 25-45% after 24 hours. Extension of the reaction time to 36 hours resulted in significantly improved yields for these compounds (Table 4.8, entries 25-30).
Isolation of these compounds was uncomplicated, and only simple recrystallization techniques were required in order to obtain samples of high purity.
Scheme 4.12. General route for the synthesis of the target benzenesulfonates
O
O
S O
O O-K+ X
O H
O
O
S O O O-K+ X
+
R R
131
Table 4.8. Yields for the formation of target molecules.
Entry Benzenesulfonate Benzaldehyde Product Yield /%
1 H (125) H (67) 3 73a
2 4-Br (63) 5 81a
3 4-Cl (70) 6 76a
4 4-F (72) 7 72a
5 4-OMe (99) 8 68a
6 3-Br (132) 9 73a
7 3-Cl (133) 43 78a
8 3-F (134) 44 76a
9 2-Br (135) 10 66a
10 2-Cl (74) 45 68a
11 2-F (136) 46 71a
12 2-OMe (100) 47 64a
13 4-F (126) 67 11 68a
14 63 48 71a
15 70 49 67a
16 72 17 70a
17 99 50 54a
18 132 51 63a
19 133 52 64a
20 134 53 69a
21 135 23 62a
22 74 54 67a
23 136 55 68a
24 100 56 66a
25 4-Cl (127) 67 12 69b
26 99 57 65b
27 134 58 61b
28 74 59 60b
29 136 18 62b
30 100 24 59b
asulfonate (1 mmol), benzaldehyde (1 mmol), KOH (2 mmol), EtOH, rt, 24 h bsulfonate (1 eq), benzaldehyde (1 mmol), KOH (3 eq), EtOH, rt, 36 h.
132