FACTORES QUE AFECTAN LA VELOCIDAD DE PENETRACIÓN

2.1.1. Introduction

As mentioned in the general introduction, CeCl3 is commonly used to activate carbonyl groups

towards the attack of an organomagnesium reagent. However, the low solubility of CeCl3 in THF

requires the use of stoichiometric amounts of this relatively expensive salt. The general problem of insolubility of the lanthanide salt is elegantly solved by using the THF-soluble complex LaCl3·2LiCl. Recently, this method was applied to the synthesis of tryptamines and related

heterocycles.120, 121 However,LaCl3·2LiCl has been used so far only in stoichiometric amounts,

while a catalytic version of this reaction would be highly appreciable considering industrial applications of this methodology.122

2.1.2. LaCl3·2LiCl-catalyzed addition of organomagnesium reagents to enolizable ketones A comparative study of the use of LaCl3·2LiCl in stoichiometric and catalytic amounts for 1,2-

addition reactions of various Grignard reagents to ketones was investigated (Scheme 2).

Scheme 69: Addition of Grignard reagents (28a-j) to ketones (58c-j) in the presence of variable

amount of LaCl3·2LiCl.

Therefore, organomagnesium reagents of type 28 were added to ketones of type 58 premixed with either 100 mol% or 30 mol% of LaCl3·2LiCl or in the absence of the lanthanum salt.

Lowering the amount of LaCl3·2LiCl below 30 mol% often resulted in heterogeneous reaction

mixtures. Thus, the reaction of cyclohexylmagnesium bromide (28b) with the easily enolizable

120

(a) K. C. Nicolaou, A. Krasovskiy, U. Majumder, V. E. Trepanier, D. Y.-K. Chen, J. Am. Chem. Soc. 2009, 131, 3690; (b) K. C. Nicolaou, A. Krasovskiy, V. E. Trepanier, D. Y.-K. Chen, Angew. Chem. Int. Ed. 2008, 47, 4217.

121 _{For the prepartion of aryl- and heteroaryl-lanthanum reagents by directed ortho-metalation reactions, see: S. H.}

Wunderlich, P. Knochel, Chem. Eur. J. 2010, 16, 3260.

122 _{The addition of Grignard reagents to imines requires only 10 mol% of LaCl}

3·2LiCl. An isolated example of the

B. Results and Discussion 68 ketone 58c in the presence of one equivalent of LaCl3·2LiCl provided the tertiary alcohol 98a in

93% yield (entry 1 of Table 16). By using 30 mol% of LaCl3·2LiCl a similar yield (87%) was

achieved. Without the addition of LaCl3·2LiCl only 33% of the alcohol 98a was isolated.

Table 16: Addition of Grignard reagents to different ketones in the presence of LaCl3·2LiCl.

Entry Grignard

reagent Ketone Product

Yield (%)a in the presence of variable amounts of LaCl3·2LiCl

100 mol% 30 mol% 0 mol%

1 28bc 58c 98a 93 87 33b 2 28cd 58d 98b 86 65 <3 3 28dd 58e 98c 95 94 69 4 28ed 58d _98d 97 93 67b 5 28fe 58f 98ef 76 66 22 6 28ge 30 98f 72 72 13 7 28he 58g 98g 77 84 87 8 28ie 58h 98h 76 83 81

B. Results and Discussion 69 Table 16 continued 9 28je 58i 98i 73 74 84 10 28ae 58c _98jf 71 67 22 11 28fe 58j 98k 59 65 75

[a] Yield of isolated analytically pure product. [b] Yields determined by 1H-NMR. [c]TheGrignard reagent was prepared by direct magnesium insertion in the presence of LiCl according to ref.117. [d] The Grignard reagent is commercially available. [e]The Grignard reagent was prepared by halogen-magnesium exchange reaction using

i-PrMgCl·LiCl according to ref. 118. [f] Experiments were performed by Dr. Andrei Gavryushin and are given

here for the sake of completeness.

The reaction of the secondary alkylmagnesium reagent i-PrMgCl (28c) with 1,3-diphenylacetone (58d) is strongly influenced by the addition of LaCl3·2LiCl. Thus, the alcohol 98b was obtained

in 86% with stoichiometric amount of LaCl3·2LiCl and in 65% yield in the presence of 30 mol%

of LaCl3·2LiCl (entry 2). In the absence of LaCl3·2LiCl, only traces of the alcohol 98b were

obtained due to the occurrence of competing reduction and enolization reactions. With MeMgCl (28d) which does not possess β-hydrogen atoms, similar yields were obtained regardless of the amount of the lanthanum salt added (entry 3). Reaction of phenylmagnesium chloride (28e) with the enolizable ketone 58d led to the desired alcohol 98d in 93-97% in the presence of either 30 or 100 mol% of LaCl3·2LiCl (entry 4). Without LaCl3·2LiCl, a yield of 67% was achieved. In the

reaction of naphthylmagnesium chloride (28f) with the less sterically hindered cyclohexyl methyl ketone (58f), the influence of LaCl3·2LiCl is relatively strong (entry 5). The uncatalyzed reaction

afforded the product 98e in 22% yield, in the presence of 30 mol% of LaCl3·2LiCl a yield of 66%

was obtained. Using stoichiometric amounts of LaCl3·2LiCl led to the product 98e in 76% yield.

In the absence of a catalyst, sterically hindered Grignard reagents do not react satisfactorily with ketones bearing acidic protons. Thus, reaction of 2-(trifluoromethyl)phenylmagnesium chloride (28g) and acetophenone (30) furnished the corresponding alcohol 98g in 72% yield only in the presence of LaCl3·2LiCl, independently on whether 100 or 30 mol% were used (entry 6). A poor

yield of 98f (13%) was observed in the absence of LaCl3·2LiCl. Treatment of dicyclopropyl

B. Results and Discussion 70 organomagnesium reagents 28h-j led to the desired alcohols 98g-i in similar yields almost regardless of the LaCl3·2LiCl amount (entries 7-9). However, the positive influence of

LaCl3·2LiCl was well demonstrated in the case of heteroaromatic organomagnesium compounds

such as 2-pyridylmagnesium chloride (28a; entry 10). Its reaction with ketone 58c led to the desired alcohol 98j in 71% yield only in the presence of LaCl3·2LiCl. Using electron-rich

arylmagnesium reagent 28f and enolizable ketone 58j the alcohol 98k was obtained in lower yields with LaCl3·2LiCl than without the use of LaCl3·2LiCl (entry 11). These results show that

for the addition of electron-rich organomagnesium species the influence of LaCl3·2LiCl on the

product yield can be negative.

An upscaling of the above described procedure gave satisfactory results (Scheme 70). The reaction of ketone 58d either with secondary alkylmagnesium reagent 28c in the presence of LaCl3·2LiCl (100 mol%) or with aryl magnesium reagent 28e in the presence of LaCl3·2LiCl (30

mol%) furnished the expected alcohols 98b and 98d in 83-88% yield.

RMgCl (1.1 equiv) LaCl3—2LiCl (30-100 mol%)

THF, 0 °C to 25 °C Ph Ph O Ph Ph OH R 58d

R=i-Pr: (98b): 83% (100 mol% LaCl3—2LiCl)

Ph: (98d): 88% (30 mol% LaCl3—2LiCl)

98b-d

Scheme 70: Upscaled reaction (20 mmol) of ketone 58d with either i-PrMgCl (28c) using

B. Results and Discussion 71

2.2. Addition of functionalized organozinc reagents to aldehydes, ketones and carbon