Chemoselective efficient synthesis of functionalized β-oxonitriles through cyanomethylation of Weinreb amides

Article abstract of DOI:10.1039/c4ob02398f

A synthesis of β-oxonitriles is reported via the generation of R¹R²CLiCN species followed by the trapping with variously decorated Weinreb amides. The optimization study revealed that lithiation of acetonitriles is best accomplished by deprotonation with MeLi-LiBr at low temperature. The protocol can be conveniently adapted to the synthesis of α-mono or α,α-disubstituted cyanoketones. ¹⁵N- and ¹⁷O-NMR data are reported for selected compounds. This journal is

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DOI: 10.1039/C4OB02398F
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ARTICLE TYPE
Chemoselective Efficient Synthesis of Functionalized β-oxonitriles
through Cyanomethylation of Weinreb Amides
Ashenafi Mamuye Damtew,a,b‡ Laura Castoldi,a‡ Ugo Azzena,b Wolfgang Holzera and Vittorio Pacea*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
limitation affects the oxidative coupling strategy recently
described by Liu and co-workers.12
Scheme 1. Summary of available methods to access β-oxonitriles.
A synthesis of β-oxonitriles is reported via the generation of
R1R2CLiCN species followed by the trapping with variously
decorated Weinreb amides. The optimization study revealed
that lithiation of acetonitriles is best accomplished by
O
10 deprotonation with MeLi-LiBr at low temperature. The
protocol can be conveniently adapted to the synthesis of α-
mono or α,α-disubstituted cyanoketones. 15N- and 17O-NMR
data are reported for selected compounds.
O
X
R
OR1
R
(a)
(b)
CN
MCH2CN
55
O
O
OH
CN
(f)
(c)
Ar
Br
CN
CN
R
CN
+
R
In
DMP
R
15 β-Oxonitriles, also referred as α-cyanoketones, are valuable
synthons in organic synthesis because of the multiple
manipulations that both the carbonyl and the nitrile functionalities
can undergo.1 In this sense, they represent useful building blocks
for the construction of biologically active heterocycles such as
20 HIV inhibitors2 or anti-inflammators.3 Moreover, stereoselective
reductions of the ketone moiety would afford enantiopure β-
hydroxynitriles4 that are versatile scaffolds in the synthesis of
important drugs such as the antidepressants (S)-fluoxetine5
(Prozac®) and (S)-duloxetine6 (Cymbalta®). Thus, the synthesis of
25 this motif has been object of several studies during the years and
a closer examination allows to include them in the following
main categories (Scheme 1): a) homologation of a given carbonyl
precursor (i.e. ester) with a metalated cyanomethyl carbanion
(MCH2CN, M = Li, MgHal, K, Na, Sm);7 b) nucleophilic
30 substitution with the highly toxic cyanide anion on an α-
haloketone;8 c) oxidation of a cyanohydrin;9 d) Pd-catalysed
carbonylation of aryl iodides and TMSCH2CN10 or unactivated
nitriles;11 e) Cu-catalysed oxidative coupling of aromatic alcohols
and CH3CN;12 f) In-mediated coupling of bromoacetonitriles with
35 acyl cyanides;13 g) C-arylation of resin-bound cyanoacetates.14
Historically, the homologation strategies have constituted the
method of choice because of the conceptually simplicity of the
process and the easy availability of the required reagents (a
carboxylic acid derivative and CH3CN). However, this significant
40 advantage compared to other procedures, has been limited
severely by the lack of general applicability to sensitive
carboxylic esters and by non-uniform efficiency in terms of
reaction yields. Recently, Trenkle and co-workers reported that
by deprotonating acetonitrile with KOt-amyl, reaction yields can
45 be improved, though the scope is rather limited in terms of both
esters and substituted acetonitriles:7c in particular, disubstituted
ones (i.e R1R2CHCN) have not been employed. Moreover, the
higher reactivity displayed in Pd-catalysed carbonylations by aryl
iodides compared to aliphatic counterparts renders it applicable
50 only to the synthesis of aromatic α-cyanoketones.10 An analogous
Sonication
(e)
(d)
CuCl2, KOH
O2, DMA
ArI, CO
Pd
Ar
OH
+
TMSCH2CN
CH3CN
Considering the exceptional nucleophilic properties of metalated
60 nitriles,15 as highlighted in a series of illuminating works by
Fleming and collaborators,1c,7j,15b,16 we decided to investigate the
reaction by considering simultaneously the effects of i) the
electrophilic carboxylic derivative used for the homologation and
ii) the nature of the metalated nitrile. Recently our group
65 demonstrated that Weinreb amides,17 due to the stability of the
tetrahedral intermediate generated upon reaction with an
organometallic reagent, are well-suited placeholders18 for
reactions involving α-halosubstituted organolithiums reagents
(e.g. LiCH2X, X = Cl, Br, I).19 In fact, the simple switching to
70 these easily-prepared substrates allows to maximize reactions’
efficiency compared to the corresponding esters or acid halides.
In this Communication we present a versatile, chemoselective,
high-yielding access to (α-substituted) α-cyanoketones through
the generation of lithiated acetonitriles followed by the trapping
75 with variously functionalized Weinreb amides. We also report
previously undisclosed 15N- and 17O-NMR data for selected
examples of this class of structures.
Commercially available methyl cinnamate (1a) was reacted with
4 equiv of LiCH2CN (generated from CH3CN (4.5 equiv) and n-
80 BuLi (4.0 equiv) giving the desired α’-cyano-α,β-unsaturated
ketone 2 in 66% yield (Table 1, entry 1). Surprisingly, in contrast
with our previous findings dealing with halomethylation of
Weinreb amides,18 we found that lowering the loading of
LiCH2CN to 1.5 equiv, an increase of 2 was noticed (entries 2-3).
85 Moreover, the addition of this lithiated species did not give any
corresponding carbinol product (as we observed in the case of
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Organic & Biomolecular Chemistry
Page 2 of 5
LiCH2Cl)18a resulting from the double addition to the ester.
LiBr
16
17
18
n-BuLi b
1.5
1.5
1.5
THF /
11 c
Further optimization revealed that MeLi-LiBr was the best base
to accomplish CH3CN deprotonation compared to other ones such
as simple MeLi, s-BuLi, LDA, LTMP, LHDMS or LiNH2
(entries 4-9). Considering MeLi-LiBr the optimal base for
generating the reacting lithiated acetonitrile, we tested the
corresponding Weinreb amide 1b: pleasingly, 2 could be obtained
in an excellent 86% isolated yield after simple washing (brine)
work-up thus, without needing to perform chromatographic
1b
1b
1b
- 78 View Article Online
DOI: 10.1039/C4OB02398F
n-BuLi d
n-BuLi e
THF /
- 78
12 c
5
THF /
- 78
7 c
10 purification (entry 10). Increasing the temperature up to 0 °C
causes a dramatic decrease of yields and the formation of
significant amounts of impurities difficult to remove by
chromatography (entries 11-12). The use of diethyl ether does not
affect the reaction at much extent (entry 13), while performing
15 the process in tert-butyl methyl ether (MTBE) or 2-
methyltetrahydrofuran (MTHF)20 significantly drops the yields
(entries 14-15). Generating LiCH2CN from ICH2CN and n-
BuLi7j,16b followed by the addition of the electrophile (entries 16-
17) or generating it under Barbier-type conditions (entry 18) did
20 not give satisfactory results with this particular substrate.
a) Isolated yields. b) 1b was added after 1 min from the end of the addition
c)
30 of n-BuLi to ICH2CN.
internal standard). 1b was added after 5 min from the end of the
addition of n-BuLi to ICH2CN. 1b was present at the beginning of the
NMR yields (1,3,5-trimethoxybenzene as
d)
e)
addition of n-BuLi to ICH2CN (i.e. “Barbier-type“ condition).
Subsequently, different α,β-unsaturated Weinreb amides were
35 subjected to the optimal reaction conditions for cyanomethylation
(Scheme 2). Substitution across the olefinic double bond is
tolerated, as ketone 4a was obtained in high yield. Interestingly,
the protocol works well also in the case of vinyl-homologue 4c.
However, the employment of such conditions (1.5 equiv of
40 LiCH2CN) to non-α,β-unsaturated Weinreb amides resulted in
lower conversion: pleasingly, we found beneficial to use an
excess of LiCH2CN (4.0 equiv) to obtain 4d in 90% yield (vs.
75% yield with 1.5 equiv of LiCH2CN). These results point out to
a comparatively high electrophilicity of the α,β-unsaturated
45 systems although, in the mean time, strongly suggest that a higher
loading of the cyanomethylating reagent may interfere with the
olefinic double bond, thus resulting in decreased yields. Aromatic
substrates are well-suitable for the transformation (4d-4j):
however, slightly decrements were observed for strong electron-
50 donating substituted ones (4f-g), compared to analogues with a
weak electron-donor (4e), or with electron-withdrawing
functionalities (4h-j). No deleterious effects were noticed in the
presence of an halogen substituent (4h, 4j) or, when
heteroaromatic nuclei (4k-l) were installed into the core of the
55 reagent. Aliphatic substrates react efficiently even in the presence
of pronounced steric congestion as in the case of a tert-butyl
group (4n) and an adamantyl moiety (4o). Pleasingly, the use of a
Weinreb amide bearing acidic hydrogens performs equally very
well: no side reactions derived from acidic-base equilibria
60 promoted by the basic homologating reagent could be observed in
the case of 4m.
Table 1. Reaction optimization.
O
O
[LiCH2CN]
CN
X
25
1a
X = OMe (
)
2
X = N(OMe)Me (1b)
Entry Substrate
Metal
[LiCH2CN]
Solvent /
Yield of
2 (%) a
reagent
equiv
Temp. (° C)
1
2
3
4
n-BuLi
4.0
THF /
-78
66
1a
1a
1a
1a
n-BuLi
n-BuLi
2.0
1.5
1.5
THF /
-78
68
69
71
THF /
-78
MeLi-
LiBr
THF /
-78
5
6
s-BuLi
LDA
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
THF /
-78
62
66
61
66
47
86
65
44
83
71
68
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
THF /
-78
7
LTMP
LHDMS
LiNH2
THF /
-78
8
THF /
-78
9
THF /
-78
10
11
12
13
14
15
MeLi-
LiBr
THF /
-78
65
MeLi-
LiBr
THF /
-40
MeLi-
LiBr
THF /
0
MeLi-
LiBr
Et2O /
-78
MeLi-
LiBr
MTBE / -78
MeLi-
MTHF / -78
2
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Organic & Biomolecular Chemistry
Scheme 2. Scope of the reaction.
50 Scheme 3. Synthesis of α-mono and α,α-disubstituted
cyanoketones from functionalized acetonitDriOleI:d1e0r.1iv03a9ti/vCe4sO. B02398F
View Article Online
CH3CN (4.5 equiv), MeLi-LiBr (4.0 equiv)
THF, -78 °C, 30 min
then add 3, -78 °C, 1.5 h
O
O
OMe
R1R2CHCN (4.5 equiv), MeLi-LiBr (4.0 equiv)
R
N
CN
R
O
5
10
15
20
25
Me
3a-q
THF, -78 °C, 30 min
NH4Cl (aq.)
O
4a-p
OMe
then add 3, -78 °C, 1.5 h
R
N
CN
R1 R2
R
Me
55
O
O
O
NH4Cl (aq.)
CN
CN
CN
3
6a-e
R1 = Me, 4-OMeC 6H4
R2 = H, Me
Me
OMe
a
a
a
4a
4b
4c
(87%)
(90%)
O
(86%)
O
O
O
O
O
CN
CN
CN
Me
CN
Me
CN
Me
CN
Me
60
MeO
t-Bu
Me
Me
Me
4d (90%)b
4e (92%)
Ph
4f (83%)
O
6a
6b
6c
(82%)
(86%)
(87%)
O
O
MeO
MeO
CN
CN
CN
O
O
Cl
4h (89%)
O
Ph
CN
CN
OMe
4g (79%)
4i (91%)
Ph
O
O
CN
CN
CN
O
S
OMe
6d (80%)
OMe
6e (77%)
65
F
4j (93%)
4k (82%)
4l (80%)
Inspired by our interest towards homologation chemistry,18-19,19d
we evaluated the reactivity of cyanoketone 4d with a stabilized
phosphorous ylide. Thus, β-cyanomethyl-β-phenyl ethyl acrylate
7 was easily obtained in high yield (Scheme 4, up). Surprisingly,
O
CN
O
O
Me
Me
CN
CN
Me
4m (84%)
4n (74%)
4o (68%)
70 neither
a lithium carbenoid nor a sulphur ylide (Corey-
Chaykovsky),24 that are well-known reagents for carbonyl
epoxidations, did react with substrate 4d.
a LiCH2CN (1.5 equiv); b 75% yield when 1.5 equiv of LiCH2CN were employed
With the aim to expand the synthetic portfolio of the
transformation, we focused on the employment of substituted
acetonitriles. Upon forming the lithiated species under the usual
Scheme 4. Attempted homologations with an α-cyanoketone.
30 conditions, a series of α,α-dimethyl-α-cyanoketones could be
obtained in very good yields with aliphatic or aromatic Weinreb
amides (6a-c, Scheme 3). This approach shows how the easy
generation of the functionalised lithiated acetonitrile may be
considered the method of choice for accessing such particular
35 cyanoketones. In fact, previously reported syntheses through the
direct α-methylation of the parent benzoylacetonitrile21 or, the
electrophilic addition of chlorosulfonyl isocyanate to ketones in
the presence of DMF,22 or the NaCN treatment of
aroylhydrazones under PTC conditions23 lack of general
40 applicability and their potential is somewhat limited by almost
uniformly modest yields. Analogously, the protocol allows the
addition of a lithiated α-arylacetonitrile in high yields (6d and 6e,
Scheme 2).
75 Finally, due to the very limited availability of 15N- and 17O-NMR
data for ß-oxonitriles,25 we herein provide the 15N NMR chemical
shifts (of C≡N) and 17O NMR chemical shifts (of C=O) of
selected representatives (Table 2). Moreover, in Table 2 are also
reported the corresponding data we measured for some related
80 structures to gain information on how minimal changes on the
structure are reflected on spectroscopic data (R1-R10).
45
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Organic & Biomolecular Chemistry
Page 4 of 5
Table 2. 17O and 15N shifts for selected cyanoketones and
synthesis of variously functionalised α-cyanoketones. Key
correlation with various α-substituted ketones.
30 features of the method are: a) uniformly high yields, without
View Article Online
necessity to purify by chromatography, depending neither on the
Entry Compound 17O (δ, ppm) 15N (δ, ppm)
DOI: 10.1039/C4OB02398F
substituted acetonitrile structure nor on the Weinreb amide used;
1
2
542
521a
536
510b
560
561
541
532
538
546
525
527
540
556
574
-
-126.0
4d
4f
b) possibility to access polysubstituted cyanomethylketones by
simply selecting the proper R1R2CLiCN carbanion; c) excellent
35 chemoselectivity found in particular systems such as α,β-
unsaturated Weinreb amides.
-126.7
3
-125.6
4j
4
-126.9
4k
5
-127.8
4n
We gratefully acknowledge the University of Vienna for
financial support and for awarding an Uni:docs fellowship to L.
40 C. We also thank the University of Sassari for a placement PhD
fellowship to A. M. D.
6
-127.5
4o
7
-
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
8
-
9
-
10
11
12
13
14
15
16
-
Notes and references
-
a
Department of Pharmaceutical Chemistry, University of Vienna,
-
45 Althanstrasse 14, Vienna, A-1090, Austria. *Corresponding author:
-
vittorio.pace@univie.ac.at
b
-
-
Department of Chemistry and Pharmacy, University of Sassari, Via
Vienna, 2 – Sassari (Italy).
‡
These Authors contributed equally to the work.
-135.3
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larger shifts, whereas congeners with aromatic (4d: 542, 4f: 521,
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4
| Journal Name, [year], [vol], 00–00
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Organic & Biomolecular Chemistry
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