Chemoselective Alkylations with N- and C-Metalated Nitriles

Article abstract of DOI:10.1021/acs.orglett.5b02481

Metalated nitriles exhibit complementary chemoselectivities in electrophilic alkylations. N-Lithiated or C-magnesiated nitriles can be prepared from the same nitrile precursor and selectively reacted with a 1:1 mixture of methyl cyanoformate and benzyl br

Full text of DOI:10.1021/acs.orglett.5b02481

Letter
pubs.acs.org/OrgLett
Chemoselective Alkylations with N- and C‑Metalated Nitriles
Xun Yang, Dinesh Nath, and Fraser F. Fleming*,†
Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, Pennsylvania 15282-1530, United States
S
* Supporting Information
ABSTRACT: Metalated nitriles exhibit complementary chemoselectivities in
electrophilic alkylations. N-Lithiated or C-magnesiated nitriles can be prepared
from the same nitrile precursor and selectively reacted with a 1:1 mixture of
methyl cyanoformate and benzyl bromide or bifunctional electrophiles through
chemoselective attack onto either an alkyl halide or a carbonyl electrophile. A
mechanistic explanation for the chemoselectivity preferences is provided that
rests on the structural and complexation differences between N- and C-
metalated nitriles.
hemoselectivity is one of the greatest challenges to efficient
complex molecule synthesis.1 The “preferential reaction of
Metalated cyclohexanecarbonitriles are ideal prototypes because
N- and C-metalated nitriles are readily prepared,8 the stereo-
selectivity trends and the N- and C- coordination preferences for
lithiated, magnesiated, and cuprated cyclohexanecarbonitriles are
well established,9 and the cyclohexanecarbonitrile core is a
prevalent motif in pharmaceuticals.10
Exploratory chemoselective alkylations employed the N-
lithiated nitrile 2a and a 1:1 ratio of methyl cyanoformate and
benzyl bromide (Scheme 2). Despite a high reactivity of both
C
a chemical reagent with one of two or more different functional
groups”2 allows bond construction with increased synthetic
efficiency because functional group protection and oxidation
adjustment is unnecessary.3 Precise functionalization is partic-
ularly advantageous in the late stages of complex syntheses where
the targets are functionally rich natural products or pharmaceut-
icals.4
Buried within the copious reactions of metalated nitriles are
sporadic examples of chemoselective alkylations.5 Selective
electrophile attack roughly correlates with the two N- and C-
metalated nitrile structures6 in which the metal is coordinated to
the nitrile nitrogen or the nucleophilic carbon, respectively
(Scheme 1). Alkylations of the N-lithiated and C-cuprated
Scheme 2. Cyclohexanecarbonitrile Alkylations
Scheme 1. Divergent Metalated Nitrile Alkylations
electrophiles, the benzylated nitrile 6a was formed exclusively.
An alternative preparation of the N-lithiated nitrile 2a, through a
sulfinyl−lithium exchange (1c → 2a, Scheme 2),8 followed by
addition of a 1:1 ratio of methyl cyanoformate and benzyl
bromide afforded the benzyl nitrile 6a in essentially the same
yield as from the LDA-initiated deprotonation. Collectively,
these alkylations imply that the diisopropylamine formed during
the deprotonation, which typically coordinates to lithiated
nitriles,11 does not play a role in determining the chemo-
selectivity.
cyclohexanecarbonitriles 2a and 4a,6 respectively, with propargyl
bromide illustrate the different electrophile preferences; the N-
lithiated nitrile 2a affords alkynenitrile 3, whereas the C-cuprated
nitrile 4a affords allene nitrile 5 (Scheme 1).7 The reactions
illustrate the potential to generate different N- and C-metalated
nitrile structures, from the same precursor, for divergent,
chemoselective alkylations.
In contrast to the alkylations of lithiated nitrile 2a,
magnesiated cyclohexanecarbonitrile 7a exhibits a complemen-
Scouting experiments to probe chemoselectivity differences
between N- and C-metalated nitriles were performed with
metalated nitriles derived from cyclohexanecarbonitrile (1a).
Received: August 28, 2015
© XXXX American Chemical Society
A
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Letter
tary chemoselectivity preference for methyl cyanoformate
(Scheme 2). Preparation of the C-magnesiated nitrile 7a by
bromine− or sulfinyl−magnesium exchange reactions (1b → 7a
and 1c → 7a, respectively),8 and addition of a 1:1 mixture of
benzyl bromide and methyl cyanoformate afforded only the
cyanoester 8a in 73% from 1b and in 96% yield from 1c.12
Alternatively, sequential deprotonation of 1a with LDA,
transmetalation with MgBr2 to form the C-magnesiated nitrile
7a, and addition of a 1:1 mixture of benzyl bromide and methyl
cyanoformate exclusively afforded the ester nitrile 8a (96%).12
Operationally, the same outcome was achieved by sequential
deprotonation of 1a with LDA, addition of i-PrMgCl, and then
addition of a 1:1 mixture of electrophiles which afforded 8a in
94%. The latter procedure is simple and uses a readily available
Grignard reagent to effect transmetalation.
Table 1. Chemoselective Alkylations with 1:1 Electrophiles
The analogous alkylations of cuprated and zincated cyclo-
hexanecarbonitriles were performed to determine if the divergent
chemoselectivity preferences were uniquely correlated with the
metal or with the C- or N-metalated nitrile structures (Scheme
3). Formation of the C-cuprated nitrile 4a, prepared through a
Scheme 3. C-Metalated Carbonitrile Alkylations
The chemoselectivity preferences of N-lithiated and C-
magnesiated nitriles in alkylations with a 1:1 mixture of methyl
cyanoformate and benzyl bromide is maintained in a series of
structurally diverse nitriles (Table 2). In general, C-magnesiated
nitriles exhibit higher selectivity for methyl cyanoformate than
the corresponding N-lithiated nitrile does for benzyl bromide.
Formation of the N-lithiated nitrile from the norbornene nitrile
1d and exposure to methyl cyanoformate and benzyl bromide
afforded only benzyl nitrile 6d; the corresponding C-
magnesiated nitrile generated the ester nitrile 8e (Table 2,
entry 1). The lithiated nitrile derived from cyclopentanecarboni-
trile (1e) selectively alkylated benzyl bromide, whereas the
sequential lithiation and alkylation of cycloheptanecarbonitrile
(1f) is relatively nonselective. In contrast, both magnesiated
nitriles derived from 5- and 7-membered cyclic nitriles exhibit a
high preference for acylation (Table 2, entries 2 and 3,
respectively). The lithiated nitrile derived from acyclic nitrile
1g alkylates stereoselectively but not chemoselectively, whereas
the lithiated nitriles obtained from acyclic nitriles 1h and 1i,
which have a diminished steric demand relative to 1g, exhibit a
greater selectivity for benzyl bromide (Table 2, compare entries 5
and 6 with entry 4). All three acyclic magnesiated nitriles derived
from 1g, 1h, and 1i exhibit a high preference for acylation with
methyl cyanoformate (Table 2, entries 4−6). Addition of 1 equiv
of LiCl to the lithiated nitrile derived from 1i, which contains a
potential chelating γ-methoxy group,14 renders the reaction
nonselective (Table 2, entry 6), suggesting disruption of an
association between the lithiated nitrile and the electrophile.
The chemoselectivity trends of electrophile pairs suggested
that C-magnesiated and N-lithiated nitriles derived from the
same nitrile should react with a bifunctional electrophile at
different electrophilic sites.15 Optimization led to chemoselective
alkylations of metalated cyclohexanecarbonitrile with the
bromoamide 9 (Scheme 4). Exposure of the lithiated nitrile
derived from 1a to bromoamide 9 led to a greater than 99:1
preference for the cyano amide 10a, whereas intercepting the
corresponding magnesiated nitrile derived from 1c preferentially
copper−bromine exchange with 1b,7 and exposure to a 1:1
mixture of methyl cyanoformate and benzyl bromide only
afforded cyanoester 8a.12 Treating the sulfinylnitrile 1c with
lithium butyldiethylzincate13 afforded a zincated nitrile,
tentatively formulated with zinc coordinated to carbon (7b),
which selectively reacted with the electrophile pair to only afford
cyanoester 8a.12 The preference of the C-magnesiated, C-
cuprated, and C-zincated nitriles to react with methyl
cyanoformate suggests that the chemoselectivity is determined
by the metal coordination site.
Having discovered the chemoselective alkylations of N- and C-
metalated nitriles with an equimolar mixture of methyl
cyanoformate and benzyl bromide, additional pairs of electro-
philes were screened for chemoselective alkylations. Early forays
indicated a general preference of the magnesiated nitrile 7a for a
range of oxygenated electrophiles whereas the lithiated nitrile 2a
had a more limited preference for alkyl halides. Exposure of the
lithiated nitrile 2a to a 1:1 mixture of benzyl bromide and benzoyl
chloride afforded only the benzylated nitrile 6a whereas the
magnesiated nitrile 7a reacted selectively with benzoyl chloride
to afford 8b (Table 1, entry 1). Addition of a 1:1 mixture of BnBr
and PhSSPh to the lithiated nitrile 2a led to a 3.0:1 preference for
alkylation with BnBr while the magnesiated nitrile 7a exhibited a
20.0:1 preference for sulfenylation (Table 1, entry 2). Efforts to
identify additional electrophiles that react preferentially with the
N-lithiated nitrile 2a led to a selective reaction with a 1:1 mixture
of allyl bromide and bromoacetophenone; the lithiated nitrile
exhibited a 5.0:1 preference for allyl bromide over bromoace-
tophenone, whereas the magnesiated nitrile 7a reacted
exclusively with bromoacetophenone to afford epoxide 8d
(Table 1, entry 3). Selective alkylation of the lithiated nitrile 2a
with an aliphatic iodide was achieved with iodohexane and ethyl
benzoate (Table 1, entry 4).
B
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Letter
a
Using the same principle, two chemodivergent alkylations
were performed with cyclohexanecarbonitrile (1a) and the
iodoester 12 (Scheme 5). Sulfinyl−lithium exchange of 1c with
Table 2. Chemoselective Metalated Nitrile Alkylations
Scheme 5. Chemoselective Iodoester Alkylations
BuLi followed by addition of iodoester 12 afforded solely the
cyanoester 10c through selective iodide displacement whereas
sulfinyl-magnesium exchange of nitrile 1a with i-PrMgCl and
alkylation with 12 afforded only the cyanoketone 11c.16
The ability of the N- and C- metalated nitrile structures to
direct the chemoselective alkylations suggests that associative
electrophile interactions control the selectivity, a notion
supported by the disruptive influence of LiCl. Addition of a
mixture of electrophiles to a lithiated nitrile likely results in
coordination of oxygen-containing electrophiles to the Lewis
acidic lithium which serves to prevent alkylation by anchoring the
electrophile remote from the nucleophilic carbon (Scheme 6,
13). Alkyl halides, being weaker Lewis bases, may be able to
directly approach the nucleophilic carbon resulting in alkylation
through 13 to 6.
Scheme 6. Mechanistic Explanation for the Chemoselectivity
C-Magnesiated nitriles likely coordinate oxygenated electro-
philes close to the nucleophilic carbon (Scheme 6, 14).
Complexation increases the carbonyl electrophilicity and the
electron density on magnesium which promotes alkylation either
through the C-magnesiated nitrile 14 or by scission of the weak
C−Mg bond to form a transient N-magnesiated nitrile or a
nitrile-stabilized carbanion. Close proximity with the activated
electrophile complex would then trigger rapid alkylation to afford
the nitrile 8. The preference of C-magnesiated nitriles for
oxygenated electrophiles does not preclude alkylations with alkyl
halides. Magnesiated nitriles are configurationally labile and
readily equilibrate from C-magnesiated to N-magnesiated nitriles
through conducted tour or ion exchange mechanisms.17
Consistent with this mechanistic suggestion, for alkylations of
the lithiated nitrile 2a with mixtures of benzyl bromide and
methyl cyanoformate, increasing the ratio of methyl cyanofor-
mate from 1:1 to 2:1 through 5:1 to 10:1 results in higher ratios
of the ester 8a relative to the benzyl nitrile 6a (3.1:1, 5.0:1, and
10.1:1, respectively).
a
Addition of LiCl (1 equiv) leads to a 1.7:1 ratio of 6i/8j (88% yield).
Scheme 4. Chemoselective Alkylations with a Bromoamide
afforded 11a with trace amide 10a (24:1 ratio). An analogous
alkylation of the bromoamide 9 with cyclopentanecarbonitrile
(1e) was even more selective.16 Alkylation of lithiated cyclo-
pentanecarbonitrile with 9 only afforded the amide 10b, whereas
alkylation with chloromagnesium cyclopentanecarbonitrile
exclusively gave the bromoester 11b (Scheme 4).
Further support for the proposed chelation-derived chemo-
selectivity was gleaned from alkylations with the metalated
cyclopropanecarbonitriles 7c and 7d (Scheme 7). Generation of
the C-lithiated nitrile 7c and exposure to the bromoamide 15
afforded only the ketonitrile 8k in which the carbonyl is
selectively attacked. The reversed chemoselectivity preference,
C
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Scheme 7. Mechanistic Probe for the Chemoselectivity
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: fleming@drexel.edu.
Present Address
†Department of Chemistry, Drexel University, Philadelphia, PA
19104.
Notes
compared to other lithiated nitriles (cf. Scheme 2), is consistent
with the C-lithiated structure of cyclopropanecarbonitriles.18
The magnesiated nitrile 7d selectively acylated 15 to afford 8k.
These acylations, particularly of the lithiated nitrile 7c, are
congruent with the chemoselectivity arising from the metal
coordination site.
The role of coordination was probed through a competition
experiment with an admixture of lithiated nitrile 2a and
magnesiated nitrile 7a (Scheme 8). Addition of a solution of
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support from the National Science Foundation (CHE 1111406
and IRD) is gratefully acknowledged. The opinions expressed in
this manuscript are those of the authors and do not necessarily
reflect the views of the NSF.
REFERENCES
■
Scheme 8. Metalation Crossover Experiment
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(8) Nath, D.; Fleming, F. F. Chem. - Eur. J. 2013, 19, 2023.
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(10) Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook, B. C. J.
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(11) Carlier, P. R.; Lo, C. W.-S. J. Am. Chem. Soc. 2000, 122, 12819.
(12) 1H NMR analysis was unable to detect the benzylated nitrile 6a in
the crude reaction mixture.
(13) Merkel, S.; Stern, D.; Henn, J.; Stalke, D. Angew. Chem., Int. Ed.
2009, 48, 6350.
7a to lithiated nitrile 2a, formed by sulfinyl−magnesium and
sulfinyl−lithium exchange, respectively, followed by an equi-
molar mixture of methyl cyanoformate and benzyl bromide
afforded 65% of the ester 8a and 10% of the benzyl nitrile 6a
(8a:6a = 6.5:1). The product ratio suggests predominant
alkylation via a magnesiated nitrile, possibly through trans-
metalation with magnesium halide released after alkylation or
through a dialkylmagnesium species. Insight into the potential
identity of the intermediate was gained by 13C NMR analysis of
the species formed by addition of the lithiated cyclohexane-
carbonitrile (2a) to the magnesiated nitrile 7a. The diagnostic
13C chemical shift6 of the nitrile carbon of 7a (δ = 129.63) shifted
slightly to δ = 129.10 upon addition of lithiated nitrile 2 (δ =
164.81), suggesting selective acylation via the dialkylmagnesium
16.
In summary, chemoselective alkylations of N- and C-metalated
nitriles allow preferential nucleophilic attack with different
electrophiles. For comparable alkylations from the same nitrile
precursor, N-lithiated nitriles prefer to react with alkyl halides,
whereas C-magnesiated nitriles preferentially alkylate oxy-
genated electrophiles. Alkylations with bis-electrophiles allow
selective attack at different electrophilic sites simply by judicious
choice of the metal cation. The chemoselective alkylations of
metalated nitriles offers the possibility of selective, late-stage
alkylations of polyfunctional electrophiles for efficient syntheses
and the creation of diverse natural-product like libraries.
(14) Mycka, R. J.; Eckenhoff, W. T.; Steward, O. W.; Barefoot, N. Z.;
Fleming, F. F. Tetrahedron 2013, 69, 366.
́ ́
(15) Compare with: Cahiez, G.; Chaboche, C.; Jezequel, M.
Tetrahedron 2000, 56, 2733.
(16) Determined by 1H NMR analysis of the crude reaction mixture.
(17) Patwardhan, N. N.; Gao, M.; Carlier, P. R. Chem. - Eur. J. 2011, 17,
12250.
(18) Boche, G.; Harms, K.; Marsch, M. J. Am. Chem. Soc. 1988, 110,
6925.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02481.
1H NMR and 13C NMR spectra and experimental
procedures for all new compounds (PDF)
D
DOI: 10.1021/acs.orglett.5b02481
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