Sulfinylnitriles: Sulfinyl-metal exchange-alkylation strategies

Article abstract of DOI:10.1002/chem.201203174

Adding organolithiums, Grignard reagents, or zincates to sulfinylnitriles triggers a facile sulfinyl-metal exchange to afford N- or C-metalated nitriles. Sulfinyl-magnesium exchange-alkylations efficiently install quaternary and tertiary centers, even in

Full text of DOI:10.1002/chem.201203174

FULL PAPER
DOI: 10.1002/chem.201203174
Sulfinylnitriles: Sulfinyl–Metal Exchange–Alkylation Strategies
Dinesh Nath and Fraser F. Fleming*[a]
Abstract:
Grignard reagents, or zincates to sulfi-
nylnitriles triggers facile sulfinyl–
metal exchange to afford N- or C-
metalated nitriles. Sulfinyl–magnesium
exchange–alkylations efficiently install
quaternary and tertiary centers, even in
the case of tertiary sulfinylnitriles that
contain a highly acidic methine proton.
Adding
organolithiums,
a-Sulfinylalkenenitriles afford moder-
ately nucleophilic magnesiated nitriles,
and the reactivity can be dramatically
increased by conversion to the corre-
sponding magnesiates. The sulfinyl-
metal exchange is extremely fast, pro-
ceeds efficiently with quaternary, terti-
ary, and vinylic a-sulfinylnitriles, and
exhibits an exceptional functional
group tolerance in nitrile alkylations.
a
Keywords: alkylation
·
Grignard
reaction · nitriles · quaternary cen-
ters · sulfinyls · exchange interac-
tions
Introduction
tagonist levocabastine (2),[6] and the osteoporosis candidate
odanacatib (3).[7]
Metalated nitriles are powerful nucleophiles capable of forg-
ing highly congested carbon–carbon bonds.[1] The exception-
al nucleophilicity stems from a combination of the nitrileꢀs
small steric demand[2] and an inductive stabilization,[3] which
localizes a high charge density on the nucleophilic carbon.
Several industrial processes harness the nucleophilicity of
metalated nitriles for setting the nitrile-bearing, quaternary
centers of some pharmaceuticals[4] (Figure 1); for example,
the anticancer agent anastrazole (1),[5] the H1-receptor an-
Quaternary nitriles are typically prepared by sequential
deprotonation–alkylation sequences.[8] Alkanenitriles have
higher pKa values than comparable carbonyl functionalities,
approximately 30 for protons on the nitrile-bearing
carbon,[9] which usually necessitates deprotonation with very
strong bases. Lithium diisopropylamide (LDA) is most often
employed to deprotonate alkanenitriles,[8] and generates N-
lithiated nitriles in which lithium is coordinated to the nitrile
nitrogen.[10] Structurally distinct C-metalated nitriles can be
accessed through Grignard- or alkylcopper-induced halo-
gen–metal exchange reactions with a-chloro-,[11] a-bromo-
,
[12] and a-iodonitriles.[12] Selective access to N- or C-metalat-
ed nitriles is important because the coordination mode can
dictate different alkylation regio- and stereoselectivities
(Scheme 1, 5!4 compared to 5!6).[12]
Scheme 1. Regiodivergent alkylations of N- and C-metalated nitriles.
Figure 1. Representative quaternary, nitrile-containing pharmaceuticals.
Despite extensive use in academic[8] and industrial appli-
cations,[13] there remain several challenges to alkylating ni-
triles. The use of strong, highly nucleophilic bases for depro-
tonating alkanenitriles[8] establishes firm functional group
boundaries and precludes the incorporation of more acidic
sites within the carbon scaffold. Several ingenious catalysts
and reagent systems have been designed to address the de-
protonation, and alkylation, of acetonitrile[14] (Scheme 2, 7!
8) and activated alkanenitriles[15] (Scheme 2, 8!9; R1 =aryl
or vinyl) with mild base or base–catalyst combinations. The
[a] D. Nath, Prof. F. F. Fleming
Department of Chemistry and Biochemistry
Duquesne University
600 Forbes Ave, Pittsburgh PA 15282 (USA)
Fax : (+1)412-396-5683
E-mail: flemingf@duq.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203174.
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Scheme 3. Strategies for accessing substituted sulfinylnitriles.
Scheme 2. Alkanenitrile alkylation strategies.
challenge is to develop a functional-group-tolerant alkyla-
tion of unactivated secondary and tertiary alkylnitriles.
An equally significant, and yet largely unrecognized,
problem is the selective monoalkylation of primary alkane-
nitriles (Scheme 2, 8!9). Although strong bases can com-
pletely deprotonate alkanenitriles 8, the subsequent alkyla-
tion is typically slower than proton transfer between the al-
kylated, tertiary nitrile 9 and the metalated nitrile precursor.
Rapid proton transfer results in significant double alkylation
(8!10; R3 =R2) and recovery of unalkylated nitrile 8.[16] Se-
lectively alkylating primary alkanenitriles 8 with a modest
excess of an electrophile to generate secondary alkaneni-
triles 9 is still a challenge.
In contrast to traditional deprotonation strategies that
employ a strong base (Scheme 2, 7!10), preliminary sulfin-
yl–metal exchange reactions demonstrate a high functional-
group tolerance (Scheme 2, 12!10).[17] In addition, the use
of phenylsulfinyl acetonitrile (11a) as a precursor allows
two sequential alkylations with mild base (11a!12). Subse-
quently deploying the sulfinyl group as a latent nucleophile
by adding an organometallic reagent (12!13) permits a
third alkylation to form quaternary nitriles 10. This full ac-
count significantly expands the range of substrates and elec-
trophiles that was reported previously in the preliminary
sulfoxide–metal exchange–alkylation reaction,[17] addresses
the challenge of preparing tertiary nitriles through ex-
change–alkylation sequences with tertiary sulfinylnitriles,
and demonstrates exchange–alkylations at the sp2 centers of
sulfinylalkenenitriles.
commercially available phenylthioacetonitrile (15a) and oxi-
dizing the resulting sulfide[20] provides a third route to sulfi-
nylnitriles 12. The syntheses are complementary for access-
ing sulfinylnitriles 12 under basic (11a!12 and 14!12) or
acidic conditions (through the oxidation of 15a), which en-
sures access to sulfinylnitriles that are prone to elimina-
tion.[21]
The sulfinyl–magnesium exchange–alkylation is fast, effi-
cient, and installs quaternary centers in a range of cyclic and
acyclic nitriles (Table 1, entries 1–20 and 21–25, respective-
ly). Sequentially adding iPrMgCl and BnBr to the three- to
six-membered sulfinylnitriles 12a–12d affords the corre-
sponding quaternary nitriles in excellent yield (Table 1, en-
tries 1–4). The highly efficient sulfinyl–magnesium exchange
of the cyclopropanecarbonitrile 12a demonstrates that pre-
vious, less efficient reactions[22] do not have inherent difficul-
ties with the exchange–alkylation method but, rather, these
difficulties stem from extreme steric congestion on the cy-
clopropane ring.
The electrophile scope of the reaction was probed with
the six-membered sulfinylnitrile 12d because exchange–al-
kylation sequences can install the core cyclohexanecarboni-
trile motif that is found in several nitrile-containing pharma-
ceuticals (see, for example, levocabastine (2), Figure 1).
Intercepting the magnesiated nitrile that is derived from
12d proceeds equally well with reactive allylic and propar-
gylic bromides as it does with primary and secondary alkyl
halides (Table 1, entries 5–9). The alkylation with isopropyl
iodide is particularly significant because the sequence in-
stalls contiguous quaternary–tertiary centers (Table 1,
entry 9).
Results and Discussion
Sulfinyl exchange–alkylations of the prototype compound,
sulfinylnitrile 12d, are equally effective with ketone, acyl cy-
anide, and acid chloride carbonyl electrophiles (Table 1, en-
tries 10–14). Nucleophilic addition to benzylidene malononi-
trile, a carbonyl surrogate,[23] proceeds well, as does the ad-
dition of the electrophiles propylene oxide and diphenyl di-
sulphide (Table 1, entries 15–17). Cyclohexenone is attacked
selectively at the carbonyl carbon (Table 1, entry 11), which
is likely a consequence of strong chelation between the al-
koxymagnesium intermediate and the p-electrons of the ni-
trile,[24] which prevents equilibration to the more stable con-
jugate adduct.[25] With a choice of ketone and alkylbromide
electrophilic sites, attack occurs on the carbonyl of 2-bro-
moacetophenone to afford the epoxide 10n (Table 1,
Three complimentary syntheses of substituted sulfinylnitriles
12 have been developed (Scheme 3). Deprotonating phenyl-
sulfinylacetonitrile (11a)[18] with sodium hydride in DMF
allows a facile alkylation at room temperature. Alternative-
ly, heating 11a in THF at reflux with 1,5-dibromopentane
and cesium carbonate efficiently provides the sulfinylnitrile
12d. The use of Cs2CO3 is particularly significant because
the two sequential alkylations employ a mild base that is tol-
erated by numerous functional groups.
In cases where the nitrile 14 is available, sequential depro-
tonation and sulfinylation with methyl phenylsulfinate pro-
vides the sulfinylnitrile 12.[19] Alternatively, alkylating the
2024
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Sulfinyl–Metal Exchange–Alkylation Strategies
FULL PAPER
Table 1. Sulfinyl–magnesium exchange of quaternary sulfinylnitriles.[a]
Entry
1
Sulfinylnitrile
Electrophile
Quaternary nitrile
Yield
[%]
Entry
14
Sulfinylnitrile
Electrophile
Quaternary nitrile
Yield
[%]
93
99
88
92
2
15
3
4
5
6
7
8
9
90
16
17
18
19
20
21
22
91
77
96
96
92
94
91
96
92[b]
87
86
87
90
10
11
12
13
92[b]
23
24
25
92[b]
93[b]
94[b]
86
91[b]
90[b]
[a] Performed by sequential addition of iPrMgCl and the electrophile to a solution of the sulfinyl nitrile in THF at ꢀ788C, unless otherwise noted.
[b] Performed by the addition of iPrMgCl to a solution of the electrophile and the sulfinyl nitrile in THF at ꢀ788C.
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F. F. Fleming and D. Nath
entry 14). Bicyclic and acylic sulfinylnitriles 12e–12j inter-
cept electrophiles with efficiencies that are essentially the
same as for monocyclic sulfinyl nitriles (Table 1, entries 18–
25 and 1–17, respectively).
yl–magnesium exchange to tertiary sulfinylnitriles requires
avoiding the deprotonation of the acidic methine (pKa
ꢁ12)[26] and, if successful, equilibration with the alkylated
nitrile. Early optimization reactions with one equivalent of
iPrMgCl gave approximately equal amounts of the alkylated
nitrile 9 and the recovered sulfinylnitrile 16. On the assump-
tion that the recovered sulfinyl nitrile arises from competi-
tive deprotonation by the initially formed magnesiated ni-
trile, the use of excess iPrMgCl was probed and two equiva-
lents of iPrMgCl was found to be optimal. Typically, a solu-
tion of the sulfinylnitrile in THF at ꢀ788C was added to a
solution of iPrMgCl in THF at ꢀ788C, although adding
iPrMgCl to a solution of the sulfinylnitrile and electrophile
in THF at ꢀ788C works equally well. Maintaining the tem-
perature below ꢀ788C by adding precooled reagents is the
key parameter.
Sequential exchange–alkylations with tertiary sulfinylni-
triles that contain alkyl substituents 16a–d are equally effec-
tive (Table 2). Magnesiated nitriles generated through the
exchange reaction alkylate cyanoformates, pivaloyl chloride,
and benzoyl chloride to provide the substituted nitriles 9a,
9b, 9d, 9e, and 9 f, which contain highly acidic protons
(Table 2). The presence of the potentially coordinating me-
thoxy group in 16b does not interfere with the alkylation
(Table 2, entry 4). Compared to sulfinyl–magnesium ex-
change–alkylations of quaternary sulfinylnitriles (Table 1),
the corresponding alkylations with tertiary sulfinylnitrile are
about 20% less efficient.
Particularly remarkable is the functional group tolerance
in the exchange–alkylation. Electrophilic attack on pivaloyl
chloride and methyl cyanoformate (Table 1, entries 12, 13,
23–25) proceeds in excellent yield without any observable
addition to the newly installed carbonyl functionality. More
remarkable is the ability to perform the acylation reactions
by adding a solution of iPrMgCl to a solution of the electro-
phile and the sulfinyl nitrile in THF at ꢀ788C. The exchang-
es with substrates that contain electrophilic alkyl chloride
(12h), nitrile (12i), and ester (12j) functionalities are consis-
tent with the high functional group tolerance (Table 1, en-
tries 23–25). Not only is there no intramolecular alkylation
with the magnesiated nitrile intermediate, but there is no
proton transfer with the adjacent nitrile or ester groups of
12i and 12j, respectively.
The excellent functional group tolerance and complete
absence of competitive deprotonation in the sulfinyl–magne-
sium exchange stimulated a series of exchange reactions
with tertiary sulfinylnitriles (Table 2). Extending the sulfin-
Table 2. Tertiary sulfinylnitrile exchange–alkylations.
Although the exchange–alkylation works well with car-
bonyl electrophiles, alkylhalides were unreactive under a va-
riety of conditions. However, a transmetalation from magne-
sium to copper by the addition of catalytic CuCN allows a
smooth alkylation with benzyl bromide (Table 2, entry 3).
The exchange–alkylation with tertiary sulfinylnitriles repre-
sents a considerable improvement on current nitrile alkyla-
tion procedures[16] by enlarging the electrophile scope and
avoiding polyalkylation.
The formation of a-metalated alkenenitriles is challeng-
ing. Direct deprotonation of alkenenitriles is rather sub-
strate specific,[27] whereas bromine–magnesium exchange
with a-bromoalkenenitriles provides vinylmagnesium spe-
cies with modest nucleophilicity.[28] The challenge lies in de-
veloping a general route to a-metalated alkenenitriles that
are sufficiently nucleophilic to alkylate simple alkyl halides.
Facile access to a suitable sulfinylalkenenitrile prototype, 17,
was readily achieved by condensing phenylsulfinylacetoni-
trile with benzaldehyde (Table 3).[29] The standard addition
of iPrMgCl to 17 gives a magnesiated nitrile 18 that effi-
ciently intercepts reactive electrophiles (Table 1, entries 1–
4). Attempts to alkylate 18 with propyl iodide were unsuc-
cessful. However, the addition of two equivalents of n-BuLi
to 18 gives a significantly more reactive organometallic com-
pound, presumably a magnesiate,[28,30] that is able to very ef-
ficiently alkylate propyl iodide to form the trisubstituted ni-
trile 19e (Table 3, entry 5).
Entry[a]
Sulfinylnitrile
Electrophile[a]
Tertiary nitrile
Yield
[%]
1
2
3
4
70
72
81[c]
72[b]
5
6
7
91
73
84
[a] A solution of the sulfinylnitrile in THF at ꢀ788C was added dropwise
to a solution of iPrMgCl (2 equiv) in THF at ꢀ788C, and then the elec-
trophile was added. [b] A solution of iPrMgCl (2 equiv) in THF at
ꢀ788C was added to a solution of the sulfinylnitrile and the electrophile
in THF at ꢀ788C. [c] Catalytic CuCN (10%) was added after the sulfin-
yl–magnesium exchange and before the addition of BnBr.
Exchange–alkylations of diastereomerically pure E-17
give E/Z mixtures[31] of trisubstituted alkenenitriles 19 in
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Sulfinyl–Metal Exchange–Alkylation Strategies
FULL PAPER
Table 3. Sulfinyl–magnesium exchange of sp2-hybridized sulfinylalkeneni-
triles.
cause cyanoalkylzincs are notoriously unreactive.[33] Phenyle-
thylsulfoxide (20a) and phenylbutylsulfoxide (20b) were
both isolated from the zincate exchange protocol, indicating
that either alkyl group can initiate the exchange.
Organometallic compounds attack sulfoxides to afford
sulfurane intermediates that typically fragment with inver-
sion of stereochemistry at sulfur.[34] For the sulfinyl nitriles
12, the organometallic compounds may complex with the
sulfoxide oxygen[35] in 21 to facilitate nucleophilic attack on
sulfur (Scheme 5). Concerted collapse of the sulfurane 22 to
Entry
Electrophile
Alkenenitrile
Yield (E/Z)
[%]
1
2
3
4
5
86 (7:1)
84 (2:1)
88 (2:1)
85 (>19:1)
82[a] (2:1)
6
78 (>19:1)
Scheme 5. Mechanism of sulfinyl–metal exchange.
[a] Two equivalents of n-BuLi were added to 18 prior to the addition of
PrI.
three out of five alkylations. Only with the reactive electro-
philes CD3OD and acetophenone is one diastereomer pro-
duced (Table 3, entries 4 and 6). Presumably, the magnesiat-
ed nitrile 18 is prone to E/Z equilibration[27d] that results in
a loss of stereochemical integrity in the slow alkylations
with less reactive electrophiles. The constant 2:1 ratio of dia-
stereomers of 19b, 19c, and 19e is consistent with equilibra-
tion to a 2:1 ratio of magnesiated nitrile diastereomers.
The successful sulfinyl–magnesium exchange–alkylations
stimulated the exploration of other organometallics to vary
the counter ion in the resulting metalated nitriles. The se-
quential addition of n-BuLi and cinnamyl bromide to the
prototypical sulfinylnitrile 12d gave a 90% yield of the qua-
ternary nitrile 10 f (Scheme 4). Although neither ethylzinc
iodide nor diethylzinc were able to exchange with the sulfin-
yl group, lithium butyldiethylzincate[32] generates a reactive
nucleophile that is able to alkylate methyl cyanoformate,
benzyl bromide, and propyl iodide (Scheme 4). The alkyla-
tion with PrI strongly implicates a zincate intermediate be-
the N-metalated nitrile 23 benefits from minimal charge sep-
aration during the metal migration from oxygen to nitrogen
and, for the exchange with butyllithium, would directly form
an N-lithiated nitrile (23, M=Li). N-Magnesiated nitriles
(23, M=MgCl) that are generated by an exchange with
iPrMgCl rapidly equilibrate to C-magnesiated nitriles (24,
M=MgCl) through “conducted tour”[36] or ion-pair separa-
tion mechanisms.[37] The near-quantitative isolation of iPr-
SOPh (20c) is observed in all of the exchange procedures
that employ iPrMgCl,[38] whereas BuSOPh (20b) is isolated
from the corresponding reaction with n-BuLi.
The sulfinyl–metal exchange reaction is extremely fast.
Protonation experiments indicate that the exchange is com-
plete within 1–2 min at ꢀ788C. Anecdotal evidence suggests
that the exchange is virtually instantaneous. Further evi-
dence for an extremely rapid exchange came from an unusu-
al deuteration experiment in which two equivalents of n-
BuLi were added to a solution of the sulfinyl nitrile 12d
(1 equiv) and deuterated methanol (2.5 equiv) in THF at
ꢀ788C [Eq. (1)]n-BuLi in equation graphic. In addition to
the recovered sulfinylnitrile 12d (60%), a remarkable
amount of butylphenylsulfoxide (20b) and deuterated[39] cy-
clohexanecarbonitrile 10z was obtained (35% of each). The
formation of 10z and 20b indicates that the sulfinyl–lithium
exchange is roughly as fast as the reaction of n-BuLi with
CD3OD.[40]
Scheme 4. Sulfinyl–metal exchange with butyllithium and butyldiethylzin-
cate.
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F. F. Fleming and D. Nath
The exchange rate is modestly influenced by the nature of
the aromatic sulfoxide substituent [Eq. (2)]. Performing the
exchange–acylation with the electron-rich methoxyphenyl-
sulfinylnitrile (12k) and methylcyanoformate gives 10l in a
virtually identical yield to that of the corresponding phenyl-
sulfinylnitrile 12d (90 vs. 91%, respectively; Table 1,
entry 12).
highly acidic proton (pKa ꢁ12). Two equivalents of iPrMgCl
are sufficient to convert tertiary sulfinylnitriles into magne-
siated nitriles that are capable of alkylating carbonyl elec-
trophiles to form ketonitriles and a-cyanoesters, which con-
tain highly acidic functionality. This strategy addresses the
long-standing difficulty of preparing tertiary nitriles without
polyalkylation.
Sulfinyl–metal exchange uniquely transforms sulfinylni-
triles into potent nucleophiles capable of new types of alky-
lations. The exceptional functional group tolerance, especial-
ly toward acidic sites, addresses the long-standing challenge
of selectively generating metalated nitriles in the presence
of carbonyl groups. Insight into the scope and mechanism
bode well for the future use of this chemistry in synthesis.
Competitive exchange processes indicate that phenylsulfi-
nylnitrile (12d) reacts faster with organometallic compounds
than methoxyphenylsulfinylnitrile (12k). Adding one equiv-
alent of iPrMgCl or n-BuLi to a 1:1 mixture of 12d and 12k
(1 equiv each) affords more phenylisopropylsulfoxide (20c)
or phenylbutylsulfoxide (20b) than the corresponding me-
thoxyphenylsulfoxide 20e [Eq. (3)] nBuLi in equation
graphic. Although speculative, the slower rate of the me-
thoxyphenylsulfoxide may reflect a steric impediment to
attack by the organometallic reagent.
Experimental Section
General procedure: A solution of the Grignard reagent (1.05 equiv) in
THF was added to a stirred solution of the sulfinylnitrile in THF at
ꢀ788C. After 5 min, the neat electrophile (1.0 equiv) was added to the
reaction and then the reaction was allowed to warm to room temperature
over 2 h. Saturated, aqueous NH4Cl was added to the crude reaction mix-
ture, which then was extracted with EtOAc, dried (MgSO4), concentrat-
ed, and purified by radial chromatography to afford the analytically pure
material. An in situ variation in which the Grignard reagent was added
to a solution of the sulfinylnitrile and the electrophile in THF at ꢀ788C
was also developed.
Acknowledgements
Financial support from the National Science Foundation (USA) is grate-
fully acknowledged (CHE 1111406 and 0808996, 0421252 HRMS, and
0614785 for NMR facilities).
Conclusion
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Sulfinylnitriles readily engage in a sulfinyl–metal exchange,
providing a powerful method for generating metalated ni-
triles. The exchange is equally efficient with organolithium,
organomagnesium, or triorganozincate organometallics, and
allows control over the counter ion in the metalated nitrile.
The exchange is extremely fast: BuLi exchanges with sulfi-
nylnitriles even in the presence of CD3OD. iPrMgCl
smoothly transforms quaternary, tertiary, and sp2 hybridized
sulfinylnitriles into C-magnesiated nitriles that intercept a
diverse array of electrophiles; and magnesiated nitriles gen-
erated by the exchange can readily install quaternary cen-
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quaternary–tertiary centers.
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quence, despite the potential for intramolecular alkylation
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Sulfinyl–Metal Exchange–Alkylation Strategies
FULL PAPER
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Received: September 6, 2012
Published online: December 23, 2012
Chem. Eur. J. 2013, 19, 2023 – 2029
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