The double addition reaction of alkoxymethyl nucleophiles to esters to generate novel polyoxygenated species

Article abstract of DOI:10.1016/j.tetlet.2010.06.047

The development of a double addition reaction of alkoxylmethyl nucleophiles to a variety of functionalized aryl and alkyl esters to give polyoxygenated products is reported. Key features include broad electrophile substrate scope and good yields. Structurally diverse nucleophiles were investigated and were found to successfully undergo diaddition. This development now allows facile access to this novel class of polyoxygenated molecules.

Full text of DOI:10.1016/j.tetlet.2010.06.047

Tetrahedron Letters 51 (2010) 4284–4286
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The double addition reaction of alkoxymethyl nucleophiles to esters
to generate novel polyoxygenated species
*
Vishal A. Verma , Ashok Arasappan, F. George Njoroge
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The development of a double addition reaction of alkoxylmethyl nucleophiles to a variety of functional-
ized aryl and alkyl esters to give polyoxygenated products is reported. Key features include broad elec-
trophile substrate scope and good yields. Structurally diverse nucleophiles were investigated and were
found to successfully undergo diaddition. This development now allows facile access to this novel class
of polyoxygenated molecules.
Received 28 April 2010
Revised 2 June 2010
Accepted 9 June 2010
Available online 15 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Double addition
Organostannane
Polyoxygenated
Alkoxymethyl
1. Introduction
numerous examples describing biologically active molecules with
this motif.13 While there exists several other methods for synthe-
The use of organometallic alkoxymethyl species as nucleophiles
in additions to carbonyl compounds is a powerful transformation,
resulting in the formation of a carbon–carbon bond while concom-
itantly introducing an ether appendage. These reactions commonly
sizing these types of products, such as nucleophilic addition to
3,4-dimethoxyisobutylene oxide14 or to 1,3-dimethoxypropan-2-
one,13c,15 these procedures limit the scope of nucleophile or
substrate.
make use of
a
-haloethers as substrates for either lithium–halogen
In order to determine the optimal conditions for the reaction,
several different conditions were screened. Initial attempts to form
a nucleophile of type 2 from methoxymethyl bromide and lithium–
halogen exchange or through Grignard formation failed. However,
the procedure of Kaufman4a worked as reported to generate the
stable organostannane, which was then successfully transmetallat-
ed to the organolithium species. This was observed utilizing
methyl benzoate as the electrophile for double addition. While
the requisite use of 2 equiv of the nucleophile at À78 °C was suc-
cessful in generating the desired double addition product 6, it
was formed as an inseparable mixture with the corresponding ke-
tone resulting from single addition (Table 1, entry 1) as well as
other unidentifiable products. Increasing the equivalents of nucle-
ophile while maintaining the temperature at À78 °C did not signif-
exchange1 or Grignard formation.2 However, attempts to form
these reagents through these methods are not always successful.3
Another strategy for the generation of these nucleophiles is
through synthesis of the corresponding
a
-stannylethers,4 followed
by facile lithium–tin exchange.5
While single additions of organometallic alkoxymethyl nucleo-
philes have been reported for a variety of eletrophiles,6 including
aldehydes,7 ketones and enones8 (1,2- and 1,4-addition), Weinreb
amides,1b pyridinium cations,3 and lactones,9 there remains a pau-
city of methods for means to effect a double addition reaction for
these functionalized nucleophiles. To date, there are only limited
examples reported for the double addition of an organostannyl alk-
oxymethyl reagent to a lactone.10 The study of the scope and gen-
erality of this transformation would be valuable, as it forms, in one
step, multiple carbon–carbon bonds while also introducing addi-
tional oxygen functionality in the form of ethers (Scheme 1). Such
polyoxygenated species may have important physiochemical prop-
erties, such as the ability to complex cations as crown ethers,11 in-
creased solubility in aqueous media, and potentially advantageous
biological activity.12 Indeed, a search through the literature reveals
RO
M
HO
R1
O
2
OR
OR
R1
OR2
1
3
* Corresponding author. Tel.: +1 908 740 2430.
Scheme 1. The generation of a polyoxygenated species from the double addition
E-mail address: vishal.verma@merck.com (V.A. Verma).
reaction of an organometallic alkoxymethyl reagent.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.047

V. A. Verma et al. / Tetrahedron Letters 51 (2010) 4284–4286
4285
Table 1
Optimization of reaction conditions for the double addition of 5 to ester 4
Table 2
Substrate scope of the double addition of 5 to a variety of aryl and alkyl esters
O
SnBu3
O
SnBu3
O
HO
HO
OMe
OMe
OMe
OMe
5
5
OMe
R
ester
BuLi
BuLi, THF
THF, -78 °C→rt
4
6
7
Entry
Method
Equivalents
Result
Entry
1
Ester
Yield
1
2
3
4
5
A
A
B
B
B
2
3
2
3
4
Mixture*
Mixture*
24%
56%
70%
O
OMe
OMe
70
53
MeO
O
Method A: À78 °C; 1.5 h. Method B: À78 °C?rt; 12 h.
ꢀ2:1 ratio of product to ketone by 1H NMR analysis of the mixture.
*
2
F3C
HO
icantly affect the outcome (entry 2). However, increasing the tem-
perature over the course of the reaction eliminated this ketone
side-product (method B). While the use of 2 equiv of the nucleo-
phile led to an incomplete reaction, steadily increasing the number
of equivalents of organostannane led to complete consumption of
the starting material and improved yields, with 4 equiv found to
give a 70% yield of the polyoxygenated product 6 (entries 3–5).
With optimized reaction conditions determined, an additional
examination of aryl esters was undertaken (Table 2). Interestingly,
while the presence of an electron-donating 4-methoxy group re-
sulted in a good yield, the presence of an electron-withdrawing
4-trifluoromethyl substituent did lower the yield (entries 1 and
2). The reaction was found to be tolerant of free alcohols, as the
presence of the 3-hydroxy group did not affect the outcome (entry
3), an important result that indicates the ability to circumvent pro-
tecting groups. However, ortho-methyl substitution of the phenyl
ring resulted in a lower yield, as well as a 17% yield of the corre-
sponding ketone. The presence of a heteroatom, a prominent motif
in pharmaceutically relevant molecules, also resulted in a moder-
ate yield (entry 5).
O
3
4
5
68
47
50
OMe
O
OMe
O
OMe
O
N
6
7
8
76
80
65
OMe
O
O
O
O
O
In addition to aryl esters, alkyl esters also successfully under-
went double addition (Table 2). Use of methyl hexanoate gave a
76% yield of the polyoxygenated product (entry 6). Impressively,
the reaction was tolerant of a sterically more demanding isopropyl
ester (80% yield), while even use of a bulky tert-butyl ester gave an
acceptable 65% yield (entries 7 and 8). As well as steric bulk in the
9
81
55
OMe
O
10
OMe
ester substituent,
were also well tolerated (entry 9). In addition to the use of satu-
rated alkyl esters, an ,b-unsaturated ester was utilized as the elec-
a-branching substituents on the alkyl group
a
trophile. Methyl 2-hexenoate underwent 1,2-double addition,
though with a slight loss in yield (entry 10).
With broad substrate scope tolerability achieved, additional
structurally diverse alkoxymethyl nucleophiles were examined
(Scheme 2). The diether organostannane 8, upon lithium–stannane
exchange, smoothly underwent double addition to methyl benzo-
ate to give the densely oxygenated alcohol 9. Double addition of
the nucleophile derived from 11 to the alkyl ester 10 provided
dibenzyl ether 12 in an acceptable yield. The addition of the benzyl
ethers is significant, as these types of products can be easily con-
verted to the polyol via benzyl deprotection.
OMe
MeO
O
SnBu3
O
HO
O
O
8
OMe
OMe
BuLi
°
THF, -78 C→rt
71%
4
9
In conclusion, the development of a novel double addition reac-
tion of alkoxymethyl nucleophiles to aryl and alkyl esters has been
achieved in good to acceptable yields. The reaction shows broad
substrate scope, amenable to sterically challenging aryl and alkyl
O
SnBu3
O
HO
11
O
OMe
BuLi
O
esters, as well as to the presence of acidic protons and a,b-unsatu-
°
THF, -78 C→rt
64%
ration. Further expansion of this reaction led to the use of more
complex organostannanes as nucleophiles, including polyethers
as well as benzyl ethers, notable for their ability to be further
12
10
Scheme 2. Use of organostannanes 8 and 11 in the double addition reaction.

4286
V. A. Verma et al. / Tetrahedron Letters 51 (2010) 4284–4286
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2. General procedure
The organostannane (2 mmol, 4 equiv) was dissolved in THF
(5 mL) in a nitrogen-flushed round-bottomed flask and cooled to
À78 °C. n-Butyl lithium (2 mmol, 4 equiv, 1.6 M in hexanes) was
added dropwise and the reaction was allowed to stir for 15 min
at À78 °C. The ester (0.5 mmol) was dissolved in THF (2.5 mL)
and added dropwise to the flask. The reaction was allowed to stir
at À78 °C for 1 h, then allowed to stir for 11 h as the flask warmed
to rt. The reaction was quenched with satd aq NH4Cl (10 mL) and
diluted with H2O (25 mL). The solution was extracted with EtOAc
(2 Â 75 mL), dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified via flash column chromatography (EtOAc/
hexanes) to give the desired product as colorless oil. No other iden-
tifiable products were isolated.
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References and notes
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