Metallation–substitution of an α-oxygenated chiral nitrile

Article abstract of DOI:10.1016/j.crci.2016.11.006

Deprotonation of a chiral alpha-oxygenated nitrile with the base 2,2,6,6-tetramethylpiperidylmagnesium chloride, TMPMgCl, gives rise to a chiral magnesiated nitrile, and this anion has sufficient configurational stability at low temperature to allow the formation of highly enantiomerically enriched substituted nitrile products after electrophilic quench.

Full text of DOI:10.1016/j.crci.2016.11.006

C. R. Chimie xxx (2016) 1e8
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Full paper/Memoire
Metallationesubstitution of an a-oxygenated chiral nitrile
Madeha R. Alshawish, Graeme Barker, Nicholas D. Measom, Iain Coldham*
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Deprotonation of a chiral alpha-oxygenated nitrile with the base 2,2,6,6-tetramethylpi-
peridylmagnesium chloride, TMPMgCl, gives rise to a chiral magnesiated nitrile, and this
anion has sufficient configurational stability at low temperature to allow the formation of
highly enantiomerically enriched substituted nitrile products after electrophilic quench.
© 2016 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Received 23 September 2016
Accepted 15 November 2016
Available online xxxx
Keywords:
Alkylation
Asymmetric synthesis
Carbanions
Enantioselectivity
Magnesium
Metallation
Synthetic methods
1. Introduction
softer metals such as palladium or ruthenium [4,5].
Therefore, there exists the possibility that nitriles could
Deprotonation next to carbonyl groups gives rise to
enolates that are one of the most extensively used carbon-
centred nucleophiles in synthetic chemistry [1]. Enolates
are planar species, so if the proton to be removed is at a
stereogenic centre then this stereochemistry present in the
original carbonyl compound will be lost. The same scenario
is possible with nitriles 1 if, on deprotonation, they form
metallated ketene-imine-type structures such as com-
pound 2 (Fig. 1). This is believed to occur in many cases,
particularly with lithium as the counterion, where the
lithium typically coordinates to the nitrogen atom of the
nitrile, although the CeN bond is thought to maintain
considerable triple bond character [2]. Indeed there is X-ray
crystallographic evidence for this structure on lithiation of
phenylacetonitrile [3]. However, examples of metallated
nitriles in which the metal resides on the carbon atom
(structure 3) are known, even for lithium but especially for
maintain their configuration on metallation, should struc-
tures of type 3 be formed directly from the chiral nitrile 1
and if this metallated species does not racemise rapidly.
The first example of such chemistry was reported by
Carlier and co-workers [6,7]. They showed that the chiral
cyclopropylnitrile 4 (Fig. 2) could be formed by bromi-
neemagnesium exchange with i-PrMgCl and reacts with
D2O to give high enantiomer ratio (er) values of the
deuterated product. Fleming and co-workers [8] have
found very different selectivities between lithiated and
magnesiated nitriles and that magnesium counterions
favour attachment to the carbon atom of the nitrile.
Therefore, we were interested in whether it might be
possible to take an acyclic chiral nitrile and carry out
enantiospecific metallation and then substitution, partic-
ularly using a base centred on the metal magnesium. We
reported our preliminary findings in this area recently in
which the chiral nitriles 5 and 6 successfully undergo such
chemistry [9]. This work originated from the observation
by Takeda et al. [10] that low er values were possible by
treatment of the nitrile 6 with lithium diisopropylamide
* Corresponding author.
E-mail address: i.coldham@sheffield.ac.uk (I. Coldham).
http://dx.doi.org/10.1016/j.crci.2016.11.006
1631-0748/© 2016 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: M.R. Alshawish, et al., Metallationesubstitution of an a-oxygenated chiral nitrile, Comptes
Rendus Chimie (2016), http://dx.doi.org/10.1016/j.crci.2016.11.006

2
M.R. Alshawish et al. / C. R. Chimie xxx (2016) 1e8
high performance liquid chromatography (CSP-HPLC) (er
99:1). In addition, alcohol 8 was converted, in unoptimised
yields, to the novel compounds 10 and 11 using dime-
thoxymethane and pivaloyl chloride, respectively. These
compounds were used to probe the importance of the
carbamate-protecting group on the oxygen atom.
The key chemistry of interest is whether the compounds
6, 10 and 11 will undergo metallation and then substitution
and to what extent, if at all, the enantiopurity will be
transferred to the product. We anticipated that the mag-
nesium base TMPMgCl would be better than group 1 bases
such as LDA. However, initially we confirmed whether
metallation was successful.
Fig. 1. A generic chiral nitrile and possible metallated structures
(M ¼ metal).
Treatment of the racemic ether 10 with LDA in tetra-
hydrofuran (THF) at ꢀ78 ꢁC followed by addition of acetone
or methyl cyanoformate as the electrophile gave the ex-
pected products 12 and 13 in reasonable yields (Scheme 2).
The enantiomers of these products could be resolved by
CSP-HPLC. The best conditions reported previously for the
enantiospecific metallationequench of 5 or 6 made use of
the magnesium base TMPMgCl at ꢀ107 ꢁC [9]. However,
attempts to conduct the metallation of the ether 10 with
TMPMgCl were unsuccessful, and after addition of the
electrophile (or by using in situ MeOCOCN) only starting
material 10 was recovered. It was possible to carry out the
lithiationequench of ether (S)-10 with in situ MeOCOCN
using LDA at ꢀ107 ꢁC to give the product 13 (34% yield).
Unfortunately, this product was essentially racemic (er
52:48 by CSP-HPLC).
Fig. 2. Chiral nitriles 4e6.
(LDA) and in situ benzyl bromide. Since then Takeda and
co-workers [11] reported much improved selectivities
using more reactive electrophiles (in situ quench with acid
chlorides or ethyl cyanoformate) with the nitriles 5 and 6,
with LDA as the base. Herein, we describe further results
with the nitrile 6 and with related compounds that
demonstrate the importance of the carbamate group. With
the base TMPMgCl, we show that high er values of new
substituted products are possible after quenching with
different electrophiles [12].
2. Results and discussion
We then turned our attention to the ester 11. This
compound has a carbonyl group that could help to stabilise
the metallated intermediate, although it would not be as
good a coordinating group as the carbamate carbonyl in 5
or 6. Attempted deprotonation adjacent to the nitrile in
racemic 11 with LDA followed by addition of MeOCOCl,
MeOCOCN or acetone failed to give any of the desired
substituted products. However, addition of TMPMgCl in
THFeEt2O at ꢀ107 ꢁC and then MeOCOCN was successful
and gave the nitrile product 14 in 90% yield. The enantio-
mers of this product could be resolved by CSP-HPLC.
The nitrile 6 was prepared by a method reported by
Takeda et al. [10]. This involved conversion of the
commercially available aldehyde 7 to the cyanohydrin 8,
followed by acylation to give the ester 9 (Scheme 1).
Treatment of the ester 9 with Amano lipase from pseudo-
monas fluorescens (Amano lipase PS) effected a kinetic
resolution to give the desired alcohol 8 with a high er [13].
The data matched those reported for the (S) enantiomer
[10]. Conversion of the alcohol 8 to the carbamate 6 was
carried out with triphosgene and diisopropylamine. The er
of the product 6 was verified by chiral stationary phase
Scheme 1. Preparation of chiral nitriles 9e11.
Scheme 2. Metallation of nitrile 10.
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M.R. Alshawish et al. / C. R. Chimie xxx (2016) 1e8
3
Therefore, we screened enantioenriched nitrile 11 with
TMPMgCl at ꢀ107 ꢁC, followed after 10 min by addition of
MeOCOCN (Scheme 3). This gave the desired product 14 in
high yield but as a racemic mixture.
We then turned our attention to the carbamate 6, which
is able to undergo the desired transformation with high er
by using TMPMgCl and electrophilic quench with acetone,
MeOCOCN or BnOCOCN [9]. To extend this study, we
screened a variety of bases and some new electrophiles to
explore whether TMPMgCl was the base of choice and to
increase the scope of this chemistry.
The base screening was carried out with acetone as the
electrophile and the nitrile (S)-6 to give the substituted
product 15 (Scheme 4). The results to show the comparison
of the different bases in regard to the yield of the isolated
product 15 are shown in Table 1. We were concerned about
optimising both the yield of the product 15 and its er. In
each case the major enantiomer is that shown in Scheme 4,
in which the reaction takes place with retention of
configuration, as shown by preparation of the p-bromo-
phenyl derivative and subsequent X-ray analysis [9].
Initially we investigated the base i-PrMgCl, which was
effective for the transformation (Table 1, entries 1e6).
Using inverse addition, whereby the nitrile (S)-6 was added
to the base gave similar results to normal addition of base
to the nitrile, but perhaps with slightly improved enantio-
selectivity (compare entries 1 and 2). We therefore opted to
continue further experiments with inverse addition. The
yield was improved with excess base (compare entries 2
and 3). Remarkably, even using in situ acetone that we
expected would simply form its enolate did in fact give
some product (entry 4), although disappointingly the er
was not improved. It therefore appears that there is a rapid
partial loss of enantiopurity on metallation, although sub-
sequently the magnesiated intermediate has reasonable
configurational stability (for several minutes) at ꢀ107 ꢁC.
Two other solvents were tested but t-BuOMe gave reduced
er (entry 5) and the THFeEt2O mixture gave reduced yield
(entry 6). We then tried some other bases and found that
Bu2Mg was effective and gave similar results to i-PrMgCl
(entry 7). More promising in terms of the yield was the use
of TMPMgCl$LiCl; however, the er was poorer (entry 8).
This may be because of the presence of lithium cations that
could coordinate to the nitrogen atom of the nitrile and
start to favour a ketene-imineemetallated species. The best
results were obtained by using TMPMgCl in the absence of
LiCl. This base can be prepared readily from 2,2,6,6-tetra-
methylpiperidine (TMPH) and i-PrMgCl in THF or in Et2O
[14]. Similar results were obtained by using an excess of
this base in Et2O using inverse addition, either by rapid
addition of nitrile (S)-6 (entry 9) or by addition of (S)-6
more slowly for more than about 4 min (entries 11 and 12).
An attempt to use cyclopentyl methyl ether as the main
solvent gave a good yield but poor selectivity (entry 10).
Under the optimised conditions, we selected to add the
nitrileꢁ (S)-6 slowly to 3 equiv of TMPMgCl in Et2O at
ꢀ107 C, followed by addition of the electrophile. Reason-
able yields and er values were obtained on using alkyl
cyanoformates as the electrophile to give the products
16aec (Scheme 5). We also studied some new electro-
philes. Benzoyl chloride gave the product 17 with reduced
er. This may be because of slower reaction with the acid
chloride that allows partial racemisation of the interme-
diate organomagnesium species, or possible reaction by a
mixture of retention and inversion of configuration. How-
ever, we were pleased to find that the ketone cyclo-
pentanone was successful to give the product 18 with high
Scheme 3. Metallation of nitrile 11.
Scheme 4. Metallation of nitrile 6 and quench with acetone.
Table 1
Effect of different bases and conditions for formation of product 15.
Entry
Base
Solvent
Method
t (min)
Yield (%) 15
er (S:R)
1
2
3
4
5
6
7
8
1.2 equiv i-PrMgCl
1.2 equiv i-PrMgCl
4 equiv i-PrMgCl
4 equiv i-PrMgCl
4 equiv i-PrMgCl
4 equiv i-PrMgCl
4 equiv n-Bu2Mg
5 equiv TMPMgCl$LiCl
4 equiv TMPMgCl
3 equiv TMPMgCl
4 equiv TMPMgCl
3 equiv TMPMgCl
Et2O
Et2O
Et2O
Et2O
t-BuOMe/Et2O
THFeEt2O (1:1)
Et2O
Normal
Inverse
Inverse
Inverse
Inverse
Inverse
Inverse
Inverse
Inverse
Inverse
Inverse (4 min)
Inverse (4 min)
10
10
10
In situ
10
10
10
10
2
44
30
45
24
50
24
45
73
55
79
50
48
82:18
87:13
91:9
87:13
71:29
89:11
80:20
70:30
85:15
60:40
87:13
86:14
Et2O
Et2O
9
10
11
12
CPMEa/Et2O
Et2O
In situ
2
0.1
Et2O
a
CPME ¼ cyclopentyl methyl ether.
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M.R. Alshawish et al. / C. R. Chimie xxx (2016) 1e8
4.1. 2-(Methoxymethoxy)-4-phenylbutanenitrile (10)
To a solution of alcohol ( )-8 (1.0 g, 6.2 mmol) in dime-
thoxymethane (12 mL) was added LiBr (285 mg, 3.3 mmol)
and p-TsOH monohydrate (118 mg, 0.62 mmol), and the
mixture was heated under reflux. After 3 d, the mixture was
cooled to room temperature and the solvent was evapo-
rated. Purification by column chromatography on silica and
eluting with petroleEt2O (9:1) gave the nitrile 10 (686 mg,
54%) as an oil; RG 0.2 [petroleEt2O (9:1)]; nmax (neat)/cmꢀ1
2955, 2900,1455, 1150,1105,1090,1020; 1H NMR (400 MHz,
CDCl3)
d
¼ 7.39e7.20 (m, 5H, Ph), 4.87 (d, 1H, J ¼ 7 Hz, CH),
4.69 (d, 1H, J ¼ 7 Hz, CH), 4.35 (t, 1H, J ¼ 7.5 Hz, CH), 3.45 (s,
3H, CH3), 2.87 (t, 2H, J ¼ 7.5 Hz, CH2), 2.30e2.19 (m, 2H,
CH2); 13C NMR (100 MHz, CDCl3)
d
¼ 139.7, 128.7, 128.4,
126.5, 118.3, 95.8, 64.2, 56.3, 35.1, 30.9; HRMS (ES) found:
Mþ, 205.1112. C12H15NO2 requires Mþ 205.1103.
The enantiomers were resolved by CSP-HPLC using a
Cellulose-2 column at 1 mL minꢀ1 , ambient temperature
and detection by UV absorbance at 254 nm. Injection vol-
ume (20 m
L) of the sample was prepared in a 2 g Lꢀ1 so-
lution of 0.5% i-PrOH in hexanes. Retention times were 14.5
and 15.4 min.
Scheme 5. Metallation of nitrile (S)-6 and quench with various electrophiles
.
Eþ
In the same way as mentioned previously, the alcohol
(S)-8 (4.1 g, 25.5 mmol), dimethoxymethane (50 mL), LiBr
(1.22 g, 14.1 mmol) and p-TsOH monohydrate (507 mg,
2.67 mmol) gave, after purification by column chromatog-
raphy on silica and eluting with petroleEt2O (9:1), the
enantioselectivity (er 92:8). In addition, the electrophile
benzaldehyde gave, as an inseparable mixture, the enan-
tioenriched diastereomeric products 19a and 19b. We have
determined that the absolute configuration of the product
15 demonstrated that reaction with acetone occurs with
retention of configuration [9]. However, we have not
determined the stereochemistry of the major enantiomers
of the products 16e19. It is possible that these products are
formed after reaction with retention of configuration,
particularly using cyclopentanone that is similar to
acetone. Despite this, reactions of metallated nitrile 5 with
ethyl cyanoformate and with benzoyl chloride are known
to occur with inversion of configuration [9,11a]. Regardless
of the absolute configurations, the reactions occur with
high enantioselectivity for a selection of electrophiles, as
illustrated in Scheme 5.
nitrile (S)-10 (1.8 g, 33%) as an oil; [
a]
21 ꢀ57 (c 1.0, CHCl3);
D
other data are as mentioned previously; er 98:2 (major
peak was at 14.5 min).
4.2. 1-Cyano-3-phenylpropyl 2,2-dimethylpropanoate (11)
To a solution of alcohol ( )-8 (2.0 g, 12.4 mmol) and
DMAP (25 mgand 4-dimethylaminopyridine (DMAP) (25
mg, 2 mmol) in pyridine (126 mL) was added pivaloyl
chloride (1.67 mL, 13.7 mmol) at room temperature. After
12 h, the solvent was evaporated. Purification by column
chromatography on silica and eluting with petroleEt2O
(9:1) gave the nitrile 11 (1.0 g, 33%) as an oil; RG 0.8 [pet-
roleEt2O (9:1)]; nmax (neat)/cmꢀ1 2975, 1740, 1500, 1480,
1455, 1275, 1130, 1035; 1H NMR (400 MHz, CDCl3)
3. Conclusions
d
¼ 7.39e7.17 (m, 5H, Ph), 5.28 (t, 1H, J ¼ 7 Hz, CH), 2.85 (t,
2H, J ¼ 8 Hz, CH2), 2.32e2.20 (m, 2H, CH2),1.27 (s, 9H, t-Bu);
13C NMR (100 MHz, CDCl3)
The metallation of chiral nitriles with magnesium bases
such as TMPMgCl at low temperature occurs with signifi-
cant retention of enantiopurity. The magnesiated in-
d
¼ 176.5, 139.1, 128.8, 128.4,
126.7, 116.9, 60.5, 38.8, 33.9, 30.8, 26.9; HRMS (ES) found:
Mþ, 245.1408. C15H19NO2 requires Mþ 245.1416.
termediates can be quenched with
a
variety of
electrophiles. Better results were found with the carbamate
6 than the ether 10 or ester 11. This is likely because of the
better coordinating ability of a carbamate that can stabilise
the magnesiated intermediate through chelation of the
carbonyl oxygen atom with the magnesium. This will then
reduce the extent of loss of the metal from the stereocentre
and help to retain high levels of enantiopurity in the
substituted product after electrophilic quench.
In the same way as mentioned above, the alcohol (S)-8
(1.0 g, 6.2 mmol), DMAP (13 mg, 1.0 mmol), pyridine
(64 mL) and pivaloyl chloride (0.83 mL, 6.8 mmol) gave,
after purification by column chromatography on silica and
eluting with petroleEt2O (9:1), the nitrile (S)-11 (0.26 g,
21
17%) as an oil; [
mentioned above.
a
]
ꢀ40 (c 1.0, CHCl3); other data are as
D
4.3. 3-Hydroxy-2-(methoxymethoxy)-3-methyl-2-(2-
4. Experimental section
phenylethyl)butanenitrile (12)
Procedures and data for compounds 6e9 have been
reported [9,11a].
n-BuLi (254
to i-Pr2NH (83
mL, 0.63 mmol, 2.5 M in hexanes) was added
m
L, 0.63 mmol) in THF (2 mL) at ꢀ78 ꢁC. After
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M.R. Alshawish et al. / C. R. Chimie xxx (2016) 1e8
5
10 min, nitrile ( )-10 (92 mg, 0.45 mmol) in THF (1 mL) was
added. Then, after 10 min, acetone (72 L, 0.97 mmol) was
and evaporated. Purification by column chromatography on
silica and eluting with petroleEt2O (95:5) gave the nitrile
14 (45 mg, 90%) as an oil; RG 0.1 [petroleEt2O (9:1)]; nmax
(neat)/cmꢀ1 2975, 2935, 1750, 1455, 1280, 1255, 1125, 1105,
m
added. Next, after 30 min, the mixture was warmed to
room temperature and saturated NH4Cl(aq) (4 mL) was
added. The mixture was extracted with Et2O (3 ꢂ 10 mL).
The combined organic layers were dried (MgSO4), filtered
and evaporated. Purification by column chromatography on
silica and eluting with petroleEt2O (95:5) gave the nitrile
12 (90 mg, 70%) as an oil; RG 0.2 [petroleEt2O (95:5)]; nmax
(neat)/cmꢀ1 3055, 2985, 1420, 1265, 1015; 1H NMR
1085, 1055, 1030; 1H NMR (400 MHz, CDCl3)
d
¼ 7.38e7.19
(m, 5H, Ph), 3.87 (s, 3H, CH3), 3.00e2.87 (m, 2H, CH2),
2.50e2.39 (m, 2H, CH2), 1.32 (s, 9H, t-Bu); 13C NMR
(100 MHz, CDCl3)
d
¼ 176.5, 165.4, 138.9, 128.7, 128.4, 126.7,
115.1, 72.5, 54.0, 39.2, 38.3, 30.0, 26.7; HRMS (ES) found:
MHþ, 304.1536. C17H22NO4 requires MHþ 304.1549.
The enantiomers were resolved by CSP-HPLC using a
Cellulose-1 column at 1 mL minꢀ1, ambient temperature
and detection by UV absorbance at 254 nm. Injection vol-
(400 MHz, CDCl3)
d
¼ 7.37e7.15 (m, 5H, Ph), 5.18 (d, 1H, J ¼
7.5 Hz, CH), 4.94 (d, 1H, J ¼ 7.5 Hz, CH), 3.79 (br s, 1H, OH),
3.55 (s, 3H, CH3), 2.99e2.82 (m, 2H, CH2), 2.10e1.96 (m, 2H,
CH2), 1.37 (s, 3H, CH3), 1.29 (s, 3H, CH3); 13C NMR (100 MHz,
ume (20 m
L) of the sample was prepared in a 2 g Lꢀ1 so-
CDCl3)
d
¼ 140.8, 128.6, 128.5, 126.3, 117.3, 95.7, 86.6, 74.4,
lution of 1% i-PrOH in hexanes. Retention times were 11.8
and 13.8 min.
In the same way as mentioned above, the nitrile (S)-10
(50 mg, 0.2 mmol), TMPMgCl (2.6 mL, 0.44 mmol, 0.17 M in
56.7, 37.7, 31.3, 25.7, 23.8; HRMS (ES) found: MHþ,
264.1589. C15H22NO3 requires MHþ 264.1600.
The enantiomers were resolved by CSP-HPLC using a
Cellulose-1 column at 1 mL minꢀ1, ambient temperature
and detection by UV absorbance at 254 nm. Injection vol-
THF) and MeOCOCN (38 mL, 0.48 mmol) gave, after purifi-
cation by column chromatography on silica and eluting
with petroleEt2O (9:1), the nitrile 14 (57 mg, 92%) as an oil;
data are as given above; er 51:49.
ume (20 m
L) of the sample was prepared in a 2 g Lꢀ1 so-
lution of 2% i-PrOH in hexanes. Retention times were 19.6
and 22.2 min.
4.6. [1-Cyano-2-hydroxy-2-methyl-1-(2-phenylethyl)]propyl
4.4. Methyl 2-cyano-2-(methoxymethoxy)-4-
N,N-bis(propan-2-yl)carbamate (15) [9]
phenylbutanoate (13)
Method for Table 1, entry 10: a solution of nitrile (S)-6
(100 mg, 0.35 mmol) in dry Et2O (2 mL) was added drop-
wise for more than 4 min using a syringe pump to a solu-
tion of TMPMgCl (3.5 mL, 1.4 mmol, 0.4 M solution in Et2O)
in dry Et2O (1 mL) at ꢀ107 ꢁC. After 2 min, dry acetone
(0.12 mL, 1.75 mmol) was added. Then, after 30 min, satu-
rated NH4Cl(aq) (2 mL) was added and the mixture was
allowed to warm to room temperature. The mixture was
extracted with Et2O (3 ꢂ 5 mL). The combined organic
layers were dried (MgSO4), filtered and evaporated. Puri-
fication by column chromatography on silica and eluting
In the same way as nitrile 12, n-BuLi (254
2.5 M in hexanes), i-Pr2NH (83 L, 0.63 mmol), nitrile 10
(100 mg, 0.49 mmol) and MeOCOCN (77 L, 0.97 mmol)
gave, after purification by column chromatography on silica
and eluting with petroleEt2O (9:1), the nitrile 13 (84 mg,
66%) as an oil; RG 0.1 [petroleEt2O (9:1)]; nmax (neat)/cmꢀ1
3055, 2985, 1760, 1420, 1265, 1160, 1105, 1050; 1H NMR
mL, 0.63 mmol,
m
m
(400 MHz, CDCl3)
d
¼ 7.37e7.18 (m, 5H, Ph), 5.10 (d, 1H, J ¼
7 Hz, CH), 4.83 (d,1H, J ¼ 7 Hz, CH), 3.81 (s, 3H, CH3), 3.43 (s,
3H, CH3), 3.08e2.72 (m, 2H, CH2), 2.46e2.28 (m, 2H, CH2);
13C NMR (100 MHz, CDCl3)
d
¼ 167.1, 139.4, 128.7, 128.6,
with petroleEt2O (9:1) gave the nitrile 15 (60 mg, 50%) as
21
128.5, 126.7, 126.5, 115.6, 95.5, 76.4, 57.2, 53.8, 39.9, 30.0;
HRMS (ES) found: Mþ, 263.1170. C14H17NO4 requires Mþ
263.1158.
an oil; [
a
]
D
ꢀ8.0 (c 1.0, CHCl3); other data are as reported
[9]; er 87:13 (major peak at 15 min) was determined by
CSP-HPLC using a Cellulose-1 column at 1 mL minꢀ1
ambient temperature and detection by UV absorbance at
,
The enantiomers were resolved by CSP-HPLC using a
Cellulose-1 column at 1 mL minꢀ1, ambient temperature
and detection by UV absorbance at 254 nm. Injection vol-
254 nm. Injection volume (20 mL) of the sample was pre-
pared in a 2 g Lꢀ1 solution of 1% i-PrOH in hexanes.
ume (20
m
L) of the sample was prepared in a 2 g Lꢀ1 so-
Retention times were 15 and 17 min.
lution of 0.2% i-PrOH in hexanes. Retention times were 35.0
and 40.3 min.
4.7. Methyl 2-{[bis(propan-2-yl)carbamoyl]oxy}-2-cyano-4-
phenylbutanoate (16a) [9]
The same reaction was conducted at ꢀ107 ꢁC with nitrile
10 (100 mg, 0.49 mmol) to give the nitrile 13 (41 mg, 34%)
as an oil; data are as given above; er 52:48.
A solution of nitrile (S)-6 (50 mg, 0.17 mmol) and methyl
cyanoformate (0.05 mL, 0.52 mmol) in dry Et2OeTHF (1:1)
(0.5 mL) was added dropwise for more than 4 min using a
syringe pump to a solution of TMPMgCl (1.3 mL, 0.52 mmol,
0.4 M solution in Et2OeTHF) in dry Et2OeTHF (1:1) (2.5 mL)
at ꢀ107 ꢁC. After 30 min, saturated NH4Cl(aq) (2 mL) was
added and the mixture was allowed to warm to room
temperature. The mixture was extracted with Et2O
(3 ꢂ 5 mL). The combined organic layers were dried
(MgSO4), filtered and evaporated. Purification by column
chromatography on silica and eluting with petroleEt2O
(9:1) gave the ester 16a (25 mg, 40%) as needles; mp
4.5. 1-Cyano-3-phenylpropyl 2,2-dimethylpropanoate (14)
The nitrile ( )-10 (42 mg, 0.17 mmol) in Et2OeTHF
(0.5 mL, 1:1) was added to TMPMgCl (1.56 mL, 0.51 mmol,
0.33 M in THF) in Et2OeTHF (2.5 mL, 1:1) at ꢀ107 ꢁC. After
10 min, MeOCOCN (41 mL, 0.51 mmol) was added. Then,
after 10 min, the mixture was allowed to warm to room
temperature and then saturated NH4Cl(aq) (4 mL) was
added. The mixture was extracted with Et2O (3 ꢂ 10 mL).
The combined organic layers were dried (MgSO4), filtered
Please cite this article in press as: M.R. Alshawish, et al., Metallationesubstitution of an a-oxygenated chiral nitrile, Comptes
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6
M.R. Alshawish et al. / C. R. Chimie xxx (2016) 1e8
23
ꢁ
70e73 С; other data are as reported [9]; [
a]
þ3.0 (c 1.0,
syringe pump to a solution of TMPMgCl (1.3 mL, 0.52 mmol,
0.4 M solution in Et2OeTHF) in dry Et2OeTHF (1:1) (2.5 mL)
at ꢀ107 ꢁC. After 30 min, saturated NH4Cl(aq) (2 mL) was
added and the mixture was allowed to warm to room
temperature. The mixture was extracted with Et2O
(3 ꢂ 5 mL). The combined organic layers were dried
(MgSO4), filtered and evaporated. Purification by column
chromatography on silica and eluting with petroleEt2O
(19:1) gave the ester 16a (40 mg, 52%) as an oil; data are as
D
CHCl3); er 91:9 (major peak at 16.8 min) was determined by
CSP-HPLC using a Cellulose-1 column at 1 mL minꢀ1
ambient temperature and detection by UV absorbance at
,
254 nm. Injection volume (20 mL) of the sample was pre-
pared in a 2 g Lꢀ1 solution of 1% i-PrOH in hexanes.
Retention times were 16.8 and 20.9 min.
4.8. Ethyl 2-{[bis(propan-2-yl)carbamoyl]oxy}-2-cyano-4-
phenylbutanoate (16b) [11a]
reported [9]; [
a
]
D
23 þ12.0 (c 1.0, CHCl3); er 91:9 (major peak
at 21.4 min) was determined by CSP-HPLC using
a
From racemic nitrile 6: n-butyllithium (0.4 mL,
0.95 mmol, 2.5 M solution in hexanes) was added to dii-
sopropylamine (0.15 mL, 1.02 mmol) in Et2O (2.5 mL) at
ꢀ78 ꢁC. After 10 min, nitrile ( )-6 (50 mg, 0.17 mmol) in
Et2O (0.5 mL) was added. Then, after 10 min, ethyl cya-
noformate (0.10 mL, 1.02 mmol) was added. Next, after
30 min, the mixture was allowed to warm to room tem-
perature and saturated NH4Cl(aq) (2 mL) was added. The
mixture was extracted with Et2O (3 ꢂ 5 mL). The combined
organic layers were dried (MgSO4), filtered and evapo-
rated. Purification by column chromatography on silica
and eluting with petroleEt2O (9:1) gave the ester 16b
(50 mg, 82%) as an oil; 1H NMR (400 MHz, CDCl3)
Cellulose-1 column at 1 mL minꢀ1, ambient temperature
and detection by UV absorbance at 254 nm. Injection vol-
ume (20 m
L) of the sample was prepared in a 2 g Lꢀ1 so-
lution of 1% i-PrOH in hexanes. Retention times were 21.4
and 26.9 min.
4.10. 1-Benzoyl-1-cyano-3-phenylpropyl N,N-bis(propan-2-
yl)carbamate (17)
From racemic nitrile 6: n-butyllithium (0.79 mL,
1.9 mmol, 2.5 M solution in hexanes) was added to diiso-
propylamine (0.29 mL, 2.08 mmol) in Et2O (2.5 mL) at
ꢁ
ꢀ78 C. After 10 min, nitrile ( )-6 (100 mg, 0.35 mmol) in
d
¼
7.36e7.32 (m, 2H, Ph), 7.28e7.23 (m, 3H, Ph),
Et2O (0.5 mL) was added. Then, after 10 min, benzoyl
chloride (0.25 mL, 2.0 mmol) was added. Next, after 30 min,
the mixture was allowed to warm to room temperature and
saturated NH4Cl(aq) (2 mL) was added. The mixture was
extracted with Et2O (3 ꢂ 5 mL). The combined organics
layers were dried (MgSO4), filtered and evaporated. Puri-
fication by column chromatography on silica and eluting
with petroleEt2O (9:1) gave the ketone 17 (100 mg, 72%) as
plates; mp 127e130 ꢁC; RG 0.65 [petroleEt2O (4:1)]; nmax
(neat)/cmꢀ1 2970, 2940, 1735, 1705, 1690, 1430; 1H NMR
4.39e4.26 (m, 2H, CH2), 4.09e4.00 (m, 1H, CH), 3.80e3.73
(m, 1H, CH), 3.03e2.90 (m, 2H, CH2), 2.48e2.36 (m, 2H,
CH2), 1.35 (t, 3H, J ¼ 7 Hz, CH3), 1.32e1.25 (m, 12H, 4 ꢂ Me);
13C NMR (100 MHz, CDCl3)
d
¼ 165.6, 152.7, 139.2, 128.7,
128.3, 126.6, 116.0, 73.5, 62.9, 47.4, 46.1, 38.6, 30.4, 21.6,
21.3, 20.3, 20.2, 13.9; HRMS (ES) found: MHþ, 361.2132.
C
20H29N2O4 requires MHþ, 361.2127; data are as reported
[11a].
The enantiomers were resolved by CSP-HPLC using a
CHIRALPAK® AD column at 1 mL minꢀ1, ambient temper-
ature and detection by UV absorbance at 254 nm. Injection
(400 MHz, CDCl3)
d
¼ 8.03 (d, 2H, J ¼ 7.5 Hz, Ph), 7.58 (t, 1H,
J ¼ 7.5 Hz, Ph), 7.46 (t, 2H, J ¼ 7.5 Hz, Ph), 7.36e7.31 (m, 2H,
Ph), 7.26e7.24 (m, 3H, Ph), 3.92e3.85 (m, 1H, CH),
3.75e3.69 (m, 1H, CH), 3.14e3.01 (m, 2H, CH2), 2.71e2.64
(m, 1H, CH), 2.59e2.51 (m, 1H, CH), 1.31e1.15 (m, 12H,
volume (20 m
L) of the sample was prepared in a 2 g Lꢀ1
solution of 1% i-PrOH in hexanes. Retention times were 8.1
and 9.1 min.
From nitrile (S)-6: the nitrile (S)-6 (100 mg, 0.35 mmol)
and dry ethyl cyanoformate (0.10 mL, 1.02 mmol) in dry
Et2OeTHF (1:1) (0.5 mL) was added dropwise for more
than 4 min toTMPMgCl (3.3 mL,1.04 mmol, 0.4 M in THF) in
dry Et2OeTHF (1:1) (2.5 mL) at ꢀ107 ꢁC. After 30 min,
saturated NH4Cl(aq) (2 mL) was added and the mixture was
allowed to warm to room temperature. The mixture was
extracted with Et2O (3 ꢂ 5 mL). The combined organic
layers were dried (MgSO4), filtered and evaporated. Puri-
fication by column chromatography on silica and eluting
4 ꢂ Me); 13C NMR (100 MHz, CDCl3)
¼ 190.4, 151.9, 139.4,
d
133.3, 128.8, 128.7, 128.5, 128.3, 128.2, 126.6, 116.8, 79.6,
46.8, 46.7, 38.5, 30.8, 21.4, 21.3, 20.3,19.7; HRMS (ES) found:
MHþ, 393.2161. C24H29N2O3 requires MHþ, 393.2178.
The enantiomers were resolved by CSP-HPLC using a
Cellulose1 column at 1 mL minꢀ1, ambient temperature and
detection by UV absorbance at 254 nm. Injection volume
(20 m
L) of the sample was prepared in a 2 g Lꢀ1 solution of
1% i-PrOH in hexanes. Retention times were 15.0 and
18.7 min.
with petroleEt2O (9:1) gave the ester 16b (90 mg, 72%) as
From nitrile (S)-6: the nitrile (S)-6 (100 mg, 0.35 mmol)
and dry benzoyl chloride (0.12 mL, 1.04 mmol) in dry
Et2OeTHF (1:1) (0.5 mL) was added dropwise for more
than 4 min to TMPMgCl (3.1 mL, 1.0 mmol, 0.4 M in THF) in
dry Et2OeTHF (1:1) (2.5 mL) at ꢀ107 ꢁC. After 30 min,
saturated NH4Cl(aq) (2 mL) was added and the mixture was
allowed to warm to room temperature. The mixture was
extracted with Et2O (3 ꢂ 5 mL). The combined organic
layers were dried (MgSO4), filtered and evaporated. Puri-
fication by column chromatography on silica and eluting
23
an oil; [
a
]
þ27.0 (c 1.0, CHCl3); er 80:10 (major peak at
D
9.1 min) was determined by CSP-HPLC; other data are as
mentioned above or as reported (no specific rotation data is
given in the literature) [11a].
4.9. Benzyl 2-{[bis(propan-2-yl)carbamoyl]oxy}-2-cyano-4-
phenylbutanoate (16c) [9]
A solution of nitrile (S)-6 (50 mg, 0.17 mmol) and benzyl
cyanoformate (0.08 mL, 0.52 mmol) in dry Et2OeTHF (1:1)
(0.5 mL) was added dropwise for more than 4 min using a
with petroleEt2O (9:1) gave the ester 17 (40 mg, 40%) as
23
plates; [
a
]
þ2.0 (c 1.0, CHCl3); er 63:37 (major peak at
D
Please cite this article in press as: M.R. Alshawish, et al., Metallationesubstitution of an a-oxygenated chiral nitrile, Comptes
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M.R. Alshawish et al. / C. R. Chimie xxx (2016) 1e8
7
14.9 min) was determined by CSP-HPLC; other data are as
mentioned above.
(9:1) gave an inseparable mixture of diastereomers 19a and
19b (dr 1:1) (100 mg, 77%) as a solid; RG 0.3 [petroleEt2O
(4:1)]; nmax (neat)/cmꢀ1 3445, 2965, 2940, 2255, 1685,
4.11. 1-Cyano-1-(1-hydroxycyclopentyl)-3-phenylpropyl N,N-
bis(propan-2-yl)carbamate (18)
1455; 1H NMR (400 MHz, CDCl3)
d
¼ 7.47e7.17 (m, 10H, Ph),
5.50 (d, 0.5H, J ¼ 5 Hz, CH), 5.24 (d, 0.5H, J ¼ 6.5 Hz, CH),
4.83 (d, 0.5H, J ¼ 6.5 Hz, OH), 4.38 (d, 0.5H, J ¼ 5 Hz, OH),
4.02e3.92 (m, 1H, CH), 3.75e3.63 (m, 1H, CH), 3.02e2.77
(m, 2H, CH2), 2.59e2.23 (m, 2H, CH2), 1.32e1.27 (m, 6H,
2 ꢂ Me), 1.13e0.97 (m, 6H, 2 ꢂ Me); 13C NMR (100 MHz,
From racemic nitrile 6: TMPMgCl (3.80 mL, 1.4 mmol,
0.4 M solution in Et2O) was added to the nitrile ( )-6
(100 mg, 0.35 mmol) in Et2O (3 mL) at ꢀ78 ꢁC. After 10 min,
dry cyclopentanone (0.15 mL, 1.75 mmol) was added. Then,
after 30 min, the mixture was allowed to warm to room
temperature and saturated NH4Cl(aq) (2 mL) was added. The
mixture was extracted with Et2O (3 ꢂ 5 mL). The combined
organic layers were dried (MgSO4), filtered and evaporated.
Purification by column chromatography on silica and
eluting with petroleEt2O (9:1) gave the alcohol 18 (70 mg,
54%) as needles; mp 135e137 ꢁС; RG 0.75 [petroleEt2O
(4:1)]; nmax (neat)/cmꢀ1 3465, 2970, 2940, 1700; 1H NMR
CDCl3)
d
¼ 153.7,153.6,140.1,140.0,137.5,137.2,128.7,128.6,
128.4, 128.35, 128.3, 127.4, 126.5, 126.4, 126.35, 126.3, 117.9,
117.1, 80.7, 76.5, 75.5, 46.9, 46.5, 37.2, 35.2, 30.8, 30.7, 21.1,
21.0, 20.8, 20.3; HRMS (ES) found: MHþ, 395.2334.
C
24H31N2O3 requires MHþ, 395.2335.
The diastereomers and enantiomers were resolved by
CSP-HPLC using a Cellulose1 column at 1 mL minꢀ1
,
ambient temperature and detection by UV absorbance at
254 nm. Injection volume (20 mL) of the sample was pre-
(400 MHz, CDCl3)
d
¼ 7.34e7.30 (m, 2H, Ph), 7.25e7.22 (m,
pared in a 2 g Lꢀ1 solution of 1% i-PrOH in hexanes.
Retention times were 30.3, 38.2, 51.4 and 60.0 min.
3H, Ph), 4.47 (s, 1H, OH), 4.09e3.97 (m, 1H, CH), 3.91e3.79
(m, 1H, CH), 3.02e2.95 (m, 1H, CH), 2.88e2.79 (m, 2H, CH2),
2.31e2.23 (m, 1H, CH), 2.12e1.99 (m, 2H, 2 ꢂ CH), 1.97e1.87
(m, 2H, 2 ꢂ CH), 1.79e1.71 (m, 4H, 2 ꢂ CH2), 1.28 (d, 12H, J ¼
From nitrile (S)-6: the nitrile (S)-6 (100 mg, 0.35 mmol)
in dry Et2O (2 mL) was added dropwise for more than 4 min
to TMPMgCl (3.8 mL, 1.4 mmol, 0.4 M in Et2O) in dry Et2O
(1 mL) at ꢀ107 ꢁC. After 2 min, dry benzaldehyde (0.20 mL,
1.75 mmol) was added. Then, after 30 min, saturated
NH4Cl(aq) (2 mL) was added and the mixture was allowed to
warm to room temperature. The mixture was extracted
with Et2O (3 ꢂ 5 mL). The combined organic layers were
dried (MgSO4), filtered and evaporated. Purification by
column chromatography on silica and eluting with pet-
roleEt2O (19:1) gave an inseparable mixture of di-
7 Hz, 4 ꢂ Me); 13C NMR (100 MHz, CDCl3)
d
¼ 153.3, 140.3,
128.6, 128.3, 126.3, 118.3, 85.8, 85.7, 47.1, 46.5, 38.0, 37.9,
35.3, 31.3, 24.7, 24.0, 21.4, 20.3; HRMS (ES) found: MHþ,
373.2475. C22H33N2O3 requires MHþ, 373.2491.
The enantiomers were resolved by CSP-HPLC using a
Cellulose1 column at 1 mL minꢀ1, ambient temperature and
detection by UV absorbance at 254 nm. Injection volume
(20 m
L) of the sample was prepared in a 2 g Lꢀ1 solution of
1% i-PrOH in hexanes. Retention times were 14.4 and
20.3 min.
astereomers 19a and 19b (dr 1:1) (75 mg, 60%) as a solid;
23
[
a
]
þ6.0 (c 1.0, CHCl3); er values 92:8 and 84:16 (major
D
From nitrile (S)-6: the nitrile (S)-6 (100 mg, 0.35 mmol)
in dry Et2O (2 mL) was added dropwise for more than 4 min
to TMPMgCl (3.8 mL, 1.4 mmol, 0.4 M in Et2O) in dry Et2O
(1 mL) at ꢀ107 ꢁC. After 2 min, dry cyclopentanone
(0.15 mL, 1.75 mmol) was added. Then, after 30 min, satu-
rated NH4Cl(aq) (2 mL) was added and the mixture was
allowed to warm to room temperature. The mixture was
extracted with Et2O (3 ꢂ 5 mL). The combined organic
layers were dried (MgSO4), filtered and evaporated. Puri-
fication by column chromatography on silica and eluting
peaks at 30.3 and 38.2 min) were determined by CSP-HPLC;
other data are as mentioned above.
Acknowledgements
We thank the Libyan Ministry of Higher Education, the
Leverhulme Trust (grant RPG-056) and the University of
Sheffield for funding. We thank Miss Ruaa Talk for carrying
out the reaction (Table 1, entry 10) in cyclopentyl methyl
ether.
with petroleEt2O (9:1) gave the alcohol 18 (65 mg, 50%) as
23
needles; [
a
]
ꢀ2.0 (c 1.0, CHCl3); er 92:8 (major peak at
D
14.4 min) was determined by CSP-HPLC; other data are as
mentioned above.
Appendix A. Supplementary data
Copies of NMR spectra for all novel compounds are
provided in the Supplementary data. Supplementary data
related to this article can be found at http://dx.doi.org/10.
1016/j.crci.2016.11.006.
4.12. 1-Cyano-1-(1-hydroxybenzyl)-3-phenylpropyl N,N-
bis(propan-2-yl)carbamate (19a and 19b)
From racemic nitrile 6: isopropyl magnesium chloride
(1.20 mol, 1.4 mmol, 1.15 M solution in Et2O) was added to
nitrile ( )-6 (100 mg, 0.35 mmol) in Et2O (3 mL) at ꢀ78 ꢁC.
After 10 min, dry benzaldehyde (0.20 mL, 1.75 mmol) was
added. Then, after 30 min, the mixture was allowed to
warm to room temperature and saturated NH4Cl(aq) (2 mL)
was added. The mixture was extracted with Et2O
(3 ꢂ 5 mL). The combined organic layers were dried
(MgSO4), filtered and evaporated. Purification by column
chromatography on silica and eluting with petroleEt2O
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