Chapter 4 Divergent synthesis of Amino alcohols
4.3 Result and Discussion-
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yield of the reaction. By doing so, as expected yield of the reaction improved up to 71% (Table 4.1, entry 9. Reaction worked well without losing its efficiency when the catalyst loading further decreased up to 0.5 mol % (Table 4.1, entry 10).
When the Imine equivalents were increased from 1.5 eq to 2.0 eq and the reaction time was significantly decreased, the yield improved dramatically (Table 4.1, entry 11). The 4CzIPN catalyst has the same redox potential as Ir and can be a good substitute for metal catalysts. As a result, we believed that the reaction would proceed in the same manner with the 4CzIPN catalyst. 4 CzIPN performed excellently and produced the amino-ether product in high yield, as anticipated (Table 4.1, entry 12).
Photocatalytic oxidative deprotection of PMB ethers in Ir catalyst was recently confirmed by our laboratory. We hypothesized that since PMB and PMP ether structures are so similar, the resulting PMP ether compound could undergo oxidative cleavage and yield alcohol. The oxidation capacity of the amino-ether component PMP group ( 1.39. x V SCE). Further oxidation, with the PMPO group cleaved in an oxidative state to yield the amino alcohol element, may occur, according to our hypothesis. We observed deprotected product along with the coupling product when we conducted a reaction in non- degassed MeOH, as predicted (Table 4.1, entry 13).
We hypothesized that the cleavage of the PMP ether was caused by the oxygen in the non-degassed MeOH. Therefore, we decided to use oxidizing agents in the reaction mixture to produce the amino alcohol product. When the reaction was carried out in non-degassed MeOH in the presence of (NH4)2S2O8 and K2S2O8, the amino alcohol compound 4a was detected 42 and 58% respectively (Table 4.1, entry 14, 15). When this reaction was subjected to an oxygen atmosphere, no coupling or deprotection reaction occurred (Table 4.1, entry 16). This was mainly due to the oxidative decomposition of the starting material 2a under photocatalytic conditions.
This result implies that the coupling reaction is sensitive to the oxidative condition. To increase the yield of the reaction, we considered adding the oxidative condition in the following step, i.e., after the coupling reaction was completed. With these adopted strategies, we performed the coupling reaction in degassed MeOH under argon balloon and waited for the completion of the coupling reaction by TLC
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analysis, we introduced the oxidative environment. Using (NH4)2S2O8 and K2S2O8, the resulting amino alcohol product formed in 49% and 64 % yield (Table 4.1, entry 17, 18).
Gratifyingly, it was observed that the reaction worked excellently without the use of additives and the oxidatively deprotected amino-alcohol product was afforded in 76 % yield simply by carrying out the reaction in the air (Table 4.1, entry 19). Similarly, as expected, the 4CzIPN catalyst was able to afford the amino alcohol product in excellent yield (Table 4.1, entry 20).
Control experiments showed that the reaction did not proceed in the absence of light, or photocatalyst (Table 4.1, entry 21-23).
It is worth noting that the photocatalytic coupling reaction between imine and PMPOCH2TMS can be modulated and access to the β-amino-ether and β-amino alcohol can be obtained in a single pot without the use of any additives general PMP deprotecting reagents like CAN and DDQ. The modularity nature of this reaction can be realized simply by regulating the oxidant environment.
Hence our synthesis of β-amino ether and sequential one-pot synthesis of β-amino alcohol consists of two optimized reaction conditions which employ the Ir and 4CzIPN catalyst.
4.3.2 Substrate Scope
We explored the substrate scope of differently substituted aromatic aldimines with silane reagent (Table 4.2) Under both optimized conditions. Aromatic aldimines containing alkyl, ether, ester were worked well in the reaction condition affording the excellent yields of β -amino ether (3b-3e and 4b-4e) as well as the resulting amino alcohol products.
Later, the aromatic imines containing photolabile functional groups i.e halogens such as bromo, chloro, and fluoro substrates were tried and these substrates were tolerated well in the reaction and giving the excellent yield of the β amino ether and corresponding amino alcohol products. (3f-3j and 4f-4j).
Aldimines containing chlorine group situated at various positions of the aromatic group were tested to see the effect of differently situated chlorine substituents. Ortho, meta and para-substituted chlorine aldimines gave the best yields of the β amino ether and amino alcohols (3g-3i and 4g-4i) suggesting that this reaction is not affected by the position of the chlorine group on the aromatic aldimines.
Table 4.2
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MeO2C
NHTs
Me
NHTs
F
NHTs
Cl
NHTs AcO
NHTs NHTs
Br
NHTs NHTs
3d Ir = 85 % 4-CzIPN= 90 %
3f Ir = 81%
4-CzIPN= 93%
3i Ir = 86%
4-CzIPN= 95%
3j Ir = 78%
4-CzIPN= 86%
OR OR OR OR
OR OR OR
OR
MeO
3c Ir = 73%
4-CzIPN= 82%
3e Ir = 89 %
4-CzIPN= 92%
NHTs
3g Ir = 85%
4-CzIPN= 90%
OR
NHTs
3h Ir = 74%
4-CzIPN= 89%
OR Cl
Cl 3b
Ir = 76%
4-CzIPN= 79%
3a Ir = 83 % 4-CzIPN= 83 %
4d Ir = 79%
4-CzIPN= 81%
4i Ir = 75%
4-CzIPN= 77%
4j Ir = 70%
4-CzIPN= 75%
4c Ir = 68%
4-CzIPN= 73%
4e Ir = 80%
4-CzIPN= 82%
4g
Ir = 75%
4-CzIPN= 81%
4h Ir = 74%
4-CzIPN= 75%
4b Ir = 70%
4-CzIPN= 71%
4a Ir = 76%
4-CzIPN= 81%
Ir = 74%
4-CzIPN= 85%
MeO
NHTs
3n Ir = 75%
4-CzIPN= 77%
OR NHTs
O OR
N NHTs
OR
3l
Ir = 75%
4-CzIPN= 76%
Ph
NHTs
3m
Ir = 84%
4-CzIPN= 89%
OR BnO
BnO
NHTs OR Me
Me 3o Ir = 72%
4-CzIPN= 74%
3k Ir = 72%
4-CzIPN= 75%
NHMs OR
NHSO2Ph OR
3q Ir = 75%
4-CzIPN= 80%
3p Ir = 78%
4-CzIPN= 86%
4m Ir = 75%
4-CzIPN= 75%
4n Ir = 67%
4-CzIPN= 69%
4o Ir = 68%
4-CzIPN= 67%
4p Ir = 70%
4-CzIPN= 80%
4q Ir = 71%
4-CzIPN= 75%
4l Ir = N.R 4-CzIPN= N.R 4k
Ir = N.R 4-CzIPN= N.R
Ar NTs
PMPO TMS
2a (1 eq) 1
2.0 eq
R= PMP 3a-q R= H 4a-q 1)Ir or 4CzIPN(0.5 mol%)
Blue LED (10 W) MeOH (0.1 M), rt, Argon, 2) Air, Blue LED (10 W), RT
Ar NHTs
OR
a Reaction conditions as given in Table 4.1, reported yields are for isolated material, after the completion of the step 1 of the reaction, cap of reaction vial was opened and allowed reaction to stir open to air atmosphere.
Moreover, in the case of the para-substituted aromatic aldimines, almost quantitative yields of β- amino ethers with the 4CzIPN catalyst, thus emphasizing the orthogonal nature of the reaction (3i). Fluorine-
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containing compounds have biological and pharmacological activity. Hence preparation of the fluorine- containing compounds in addition to the amino alcohol is crucial. When we tried the aromatic aldimines containing fluoro, resulting β amino ether and amino alcohol were obtained in excellent yields (3j and 4j).
When heterocyclic aldimines were tested in the reaction condition, corresponding β amino ethers products were obtained in best yields (3k, 3l). Unfortunately, the resulting deprotection reaction of these the Β amino ether products was unstable and decomposed in the reaction condition.
Complex and bulky aromatic aldimines such as disubstituted and trisubstituted aromatic aldimines were then tested and able to furnish the resultant coupling and subsequent deprotection product smoothly (3m,3n, 3o and 4m,4n,4o).
Next, we tried the imines containing different sulphonyl groups. Aldimines derived from the methane sulphonamide, and the benzene sulphonamide was also worked well and able to give the corresponding coupled and deprotected product an excellent yield. (3p,3q and 4p,4q).