Remarkable configurational stability of magnesiated nitriles

Article abstract of DOI:10.1002/anie.201303442

Quaternary stereocenters: Chiral α-magnesiated nitriles can be formed by deprotonation and are configurationally stable at low temperature, even for acyclic examples. These can be trapped with electrophiles to give enantiomerically enriched quaternary substituted products (see scheme; TMP=2,2,6,6-tetramethylpiperidine). Copyright

Full text of DOI:10.1002/anie.201303442

Angewandte
Chemie
Communications
Asymmetric Synthesis
G. Barker, M. R. Alshawish,
M. C. Skilbeck,
I. Coldham*
&&&& — &&&&
Quaternary stereocenters: Chiral a-mag-
nesiated nitriles can be formed by
deprotonation and are configurationally
stable at low temperature, even for acyclic
examples. These can be trapped with
electrophiles to give enantiomerically
Remarkable Configurational Stability of
Magnesiated Nitriles
enriched quaternary substituted products
(see scheme, TMP=2,2,6,6-tetramethyl-
piperidine).
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DOI: 10.1002/anie.201303442
Asymmetric Synthesis
Remarkable Configurational Stability of Magnesiated Nitriles**
Graeme Barker, Madeha R. Alshawish, Melanie C. Skilbeck, and Iain Coldham*
The nitrile group is an important structural feature in many
natural products and pharmaceutical molecules used for the
treatment of a diverse range of conditions.[1] In addition,
nitriles play a key role in synthesis due to their ready
conversion to many other functional groups and due to the
ease of their deprotonation and electrophilic quench adjacent
to the nitrile group. Our interest in alkaloid synthesis using
nitrile anion chemistry[2] led us to wonder if it were possible to
control the stereochemistry of the deprotonation–quench
procedure to give enantiomerically enriched a-substituted
nitriles.[3,4]
Initial studies focused on pipecolic acid-derived nitrile 1,
which was synthesized in two steps from N-Boc-pipecolic acid
according to a literature procedure.[8] We were delighted to
find (by chiral stationary phase GC on the crude reaction
mixture) high values for the enantiomer ratio (e.r.) of the
product 2 using magnesium bases (Table 1).[9]
Table 1: Metalation–acetone quench of nitrile 1.
Fleming and co-workers have studied the diastereoselec-
tivity on alkylation of metalated nitriles, revealing differences
depending on whether a lithium or magnesium cation is
used.[5] This was ascribed to differences in the structures of the
lithiated and magnesiated intermediates.[6] With a lithium
cation, there is a preference for a planar intermediate with the
lithium coordinating to the nitrogen atom (Figure 1a). How-
Entry
Base
Order of addition
t [s]
e.r.[a]
1
2
3
4
5
6
7
iPrMgCl
iPrMgCl
normal
inverse
normal
inverse
normal
inverse
normal
5
5
5
5
5
5
600
82:18
96:4
74:26
83:17
92:8
TMPMgCl·LiCl
TMPMgCl·LiCl
TMPMgCl
TMPMgCl
TMPMgCl
93:7
91:9
[a] Enantiomer ratio determined by CSP-GC. a) Base (1.2 equiv in THF),
Et2O, À1078C, then, after time t, acetone, 30 min, then NH4Cl(aq)
.
TMP=2,2,6,6-tetramethylpiperidine.
Figure 1. Some depictions of metalated nitriles.
Two different methods of addition were tested: “normal”
addition, where the base was added to a solution of the
starting material in THF/Et2O, and “inverse” addition where
the starting material in a small amount of solvent was added
to the base. Better enantiomer ratios of product 2 were
achieved when using inverse addition, particularly in the
absence of LiCl. Remarkably, high e.r. values were obtained
even after leaving the reaction for 10 min before addition of
acetone as the electrophile (Table 1, entry 7). However, only
traces of product 2 were obtained in all cases. Due to the
inability to isolate product 2 under these conditions, we were
not able to determine its absolute stereochemistry. The low
yield may be due to the reversibility of the reaction and the
difficulty of quenching the organomagnesium species at low
temperature (see Supporting Information). Other electro-
philes gave similarly poor yields.
ever, with a magnesium cation, a C-metalated species can be
formed (Figure 1b, or Figure 1c for a separated ion pair). This
opens the possibility of forming enantiomerically enriched C-
metalated nitriles and hence the potential for a new method
for asymmetric synthesis.
At the outset of our work, the closest precedent was from
Carlier and co-workers, who found that bromine–magnesium
exchange provides a magnesiated cyclopropylnitrile that can
maintain its configuration.[7] We decided to explore the
proton abstraction of enantiomerically enriched nitriles with
magnesium bases, followed by electrophilic quench to give
enantiomerically enriched products. We report here the
preliminary results of this study that have led to the formation
of highly enantiomerically enriched substituted nitriles.
Therefore our attention turned to the nitrile 3a, first
reported by Takeda and co-workers to give very poor
enantioselectivity (e.r. < 56:44) using LDA (lithium diisopro-
pylamide; in THF, À788C) then BnBr as the electrophile,[10]
although recently found to give improved results (e.r. 74:26)
using LDA (Et2O, À988C) and in situ EtOCOCN.[11] Addition
of nitrile 3a (e.r. 99:1) to a solution of TMPMgCl (Et2O,
À1078C), followed after 2 min by addition of acetone gave
the product 4a with reasonable yield and e.r. (Scheme 1).
Repetition using the brominated substrate 3b (e.r. 97:3) gave
[*] Dr. G. Barker, M. R. Alshawish, M. C. Skilbeck, Prof. I. Coldham
Department of Chemistry, University of Sheffield
Sheffield, S3 7HF (UK)
E-mail: i.coldham@sheffield.ac.uk
[**] We would like to acknowledge The Leverhulme Trust, the Libyan
Ministry of Higher Education, and the University of Sheffield for
funding. We are grateful to Harry Adams for the single-crystal X-ray
analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303442.
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Table 2: Comparison of in situ and non-in situ quenches.
Entry
T [8C]
Method
Yield 8 [%]
e.r.[a]
Scheme 1. Metalation–acetone quench of nitriles 3. a) TMPMgCl
(4 equiv) in Et2O, À1078C, then, after 2 min, acetone, 30 min, then
NH4Cl(aq) (e.r. determined by CSP-HPLC).
1
2
3
4
À107
À107
À78
in situ
10 s
in situ
10 s
66
71
69
69
97:3
92:8
95:5
59:41
À78
[a] Enantiomer ratio determined by CSP-HPLC. a) For in situ: nitrile 7
(e.r. 99:1) and MeOCOCN added to TMPMgCl (3 equiv) in Et2O/THF
(1:1), À1078C over 4 min, then, after 10 min, NH4Cl(aq); for non-in situ:
nitrile 7 (e.r. 99:1) added to TMPMgCl (3 equiv) in Et2O/THF (1:1),
À1078C over 4 min, then, after 10 s, MeOCOCN added, then, after
the product 4b, in which single-crystal X-ray analysis revealed
that reaction had occurred with retention of configuration
(see Supporting Information).
These results are remarkable in that reasonable e.r. values
can be obtained without the need for an in situ electrophilic
quench. Therefore the organomagnesium intermediate must
have appreciable configurational stability, at least at À1078C.
Attempts to conduct the reaction at À788C gave the product
4a as a racemic mixture. As expected, however, using an
in situ electrophile gave even higher enantioselectivities
(Scheme 2). Thus, adding a mixture of the nitrile 3a and
10 min, NH4Cl(aq)
.
Scheme 2. In situ metalation quench of nitrile 3a. a) Nitrile 3a and
MeOCOCN or BnOCOCN added to TMPMgCl (3 equiv) in Et2O,
À1078C, then, after 30 min, NH4Cl(aq) (e.r. determined by CSP-HPLC).
methyl cyanoformate or benzyl cyanoformate to TMPMgCl
at À1078C resulted in the formation of the products 5 or 6
with good e.r. These reactions are assumed to proceed with
inversion of configuration based on the results below.
While conducting this work, Takeda and co-workers
reported that the less hindered nitrile 7 gave e.r. up to 90:10
using the base LDA with in situ EtOCOCN at À1148C.[11] We
therefore screened this substrate using magnesium bases. The
base iPrMgCl gave none of the desired product, however
TMPMgCl gave good results (Table 2). In situ IR spectros-
copy[12] (Figure 2) revealed that three equivalents of
Figure 2. The in situ IR 3-D (top) and 2-D plots (bottom) of the
metalation of 7 with 3 equiv TMPMgCl (added after ca. 10 min) at
=
À1078C. Lines represent the intensity of the C O stretching frequency
of 7 (peak at 1724 cmÀ1; blue line) and of metalated 7 (peak at
TMPMgCl gave complete deprotonation in less than 2 min
À1
1660 cmÀ1; red line) over time.
=
at À1078C (the C O stretch at 1724 cm for 7 is replaced
À1
=
completely by a C O stretch at 1660 cm for the metalated
compound). Best conditions were found using a mixture of
the nitrile 7 with in situ electrophile added dropwise over
4 min to TMPMgCl at À1078C. Using these conditions
resulted in the product 8 with good yield and e.r. 97:3
(Table 2, entry 1). By adding MeOCOCN after 10 s (rather
than in situ), a slightly lower e.r. was obtained (entry 2). Using
a higher temperature of À788C, high e.r. was still obtained
using the in situ method (entry 3), however racemization is
fast under these conditions and poor selectivity is obtained
without an in situ quench at À788C (entry 4). In each case the
reaction proceeds with inversion of configuration, as judged
by comparison of the specific rotation with that reported
using EtOCOCN as the electrophile.[11]
The optimized conditions were then applied to a range of
different electrophilic quenches (Table 3). The best electro-
philes were the cyanoformates (entries 1–3), which gave good
yields and excellent enantioselectivities under the in situ
conditions. Benzoyl chloride gave a good yield but only
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Table 3: Using the optimized conditions with different electrophiles.
Received: April 23, 2013
Published online: && &&, &&&&
Keywords: carbanions · configurational stability · nitriles ·
.
organomagnesium compounds · stereoselectivity
Entry
Electrophile
E
Product
Yield [%]
e.r.[a]
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1
2
3
4
5
6
7
MeOCOCN
EtOCOCN
BnOCOCN
PhCOCl
tBuCOCl
PhSSO2Ph
MeI
CO2Me
CO2Et
CO2Bn
COPh
COtBu
SPh
8
9
66
75
65
73
73
84
0
97:3
92:8
97:3
82:18
50:50
89:11[b]
–
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10
11
12
13
14
Me
[a] Enantiomeric ratio determined by CSP-HPLC. [b] Reaction conducted
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7 (e.r. 99:1) and electrophile added to TMPMgCl (3 equiv) in Et2O/THF
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.
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a moderate e.r. (entry 4), whereas pivaloyl chloride gave
racemic product (entry 5). These acid chloride electrophiles
are presumably slower reacting and give time for the
intermediate to racemize. Remarkably, the electrophile
PhSSO2Ph gave good yield and e.r., even at À788C
(entry 6), although alkyl halides such as iodomethane were
unsuccessful (entry 7). Attempts to form product 14 by
transmetalation from magnesium to copper using CuI,
CuCN or CuCN·2LiCl followed by addition of iodomethane
were also unsuccessful. The absolute configuration of the
major enantiomer of products 9 and 11 was determined by
comparison with the literature.[11] It is highly likely that
products 8 and 10 are likewise formed by inversion of
configuration. The absolute configuration of the sulfide 13
was not determined.
Kinetic experiments were conducted to determine the
rate of enantiomerization of the organomagnesium species.
By measuring the e.r. of the product 8 over time, it was
possible to determine from a first-order plot (see Supporting
Information) the value for the rate constant k ꢀ 3 ꢀ 10À4 sÀ1,
equating to a half-life for enantiomerization, t1/2 ꢀ 38 min at
À1078C. Racemization was fast at À788C and the half-life for
enantiomerization can be estimated as t1/2 ꢀ 8 s at À788C,
which fits with the data in Table 2. The organomagnesium
species has considerable configurational stability at lower
temperatures. This stability may be aided by chelation of the
magnesium to the carbonyl oxygen atom of the carbamate
group.
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nating an enantioenriched nitrile with a stereocenter a to the
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Chemie
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