Cyclic nitriles: Diastereoselective alkylations

Article abstract of DOI:10.1021/jo0501184

Diastereoselective alkylations of metalated conformationally locked 4-tert-butylcyclohexanecarbonitrile are highly diastereoselective with magnesium and copper counterions but only modestly diastereoselective with lithium as the counterion. Selective gene

Full text of DOI:10.1021/jo0501184

Cyclic Nitriles: Diastereoselective Alkylations
Fraser F. Fleming,* Subrahmanyam Gudipati, Zhiyu Zhang, Wang Liu, and
Omar W. Steward
Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, Pennsylvania 15282-1530
flemingf@duq.edu
Received January 20, 2005
Diastereoselective alkylations of metalated conformationally locked 4-tert-butylcyclohexanecarbo-
nitrile are highly diastereoselective with magnesium and copper counterions but only modestly
diastereoselective with lithium as the counterion. Selective generation of diverse metalated nitriles
is readily achieved through bromine-magnesium, -copper, and -lithium exchange reactions of
the corresponding bromonitrile or, for lithium, by deprotonating the parent nitrile with lithium
diethylamide. Collectively, high alkylation stereoselectivities correlate with the retentive alkylations
of C-metalated nitriles, whereas N-lithiated nitriles alkylate with modest selectivity, reflecting
minimal steric differences in the corresponding axial and equatorial electrophile trajectories.
R-Metalated nitriles are exceptional nucleophiles, ide-
ally suited for stereoselective alkylations.1 Alkylation
stereoselectivities are governed by the powerful inductive
2
stabilization of metalated nitriles, which minimizes
3
N-alkylation and often leads to stereoselectivities com-
plimentary to those achieved with resonance-stabilized
4
enolates. Inductive stabilization is evident from the
5
X-ray structures of metalated nitriles that consistently
exhibit short C-CN bonds (1.36-1.45 Å, Figure 1),
resulting from an electrostatic contraction between the
formal carbanion and the adjacent electron-deficient
nitrile. Analogously, minimal elongation of the CtN bond
is observed in numerous metalated nitriles, with the bond
length being only slightly elongated when compared to
the CtN bond length in neutral nitriles (1.15-1.20 and
FIGURE 1. X-ray structures of metalated nitriles.
6
in the N-metalated nitrile 1 to pyramidal in the C-
1
.14 Å, respectively).
The X-ray structures of metalated nitriles show a
7
8
metalated nitriles 2 and 4, with considerable variation
in the degree of pyramidalization, depending on the
nature of the metal and the presence or absence of
continuum of geometries for the metalated carbon.
Geometries of the metalated carbon range from planar
9
adjacent aromatic substituents. Lithiated nitriles exhibit
exclusive N-lithiation,10 whereas transition metals coor-
(
1) (a) Fleming, F. F.; Shook, B. C. Tetrahedron 2002, 58, 1. (b)
Arseniyadis, S.; Kyler, K. S.; Watt, D. S. Org. React. 1984, 31, 1.
2) Nitriles are powerful inductive stabilizing groups with weak
dinate to nitrogen or carbon with roughly equal fre-
(
delocalizing effects: (a) Richard, J. P.; Williams, G.; Gao, J. J. Am.
Chem. Soc. 1999, 121, 715. (b) Bradamante, S.; Pagani, G. A. J. Chem.
Soc., Perkin Trans. 2 1986, 1035. (c) Dayal, S. K.; Ehrenson, S.; Taft,
R. W. J. Am. Chem. Soc. 1972, 94, 9113.
(6) Zarges, W.; Marsch, M.; Harms, K.; Boche, G. Angew. Chem.,
Int. Ed. Engl. 1989, 28, 1392.
(7) Boche, G.; Harms, K.; Marsch, M. J. Am. Chem. Soc. 1988, 110,
6925.
(3) (a) Enders, D.; Kirchhoff, J.; Gerdes, P.; Mannes, D.; Raabe, G.;
(8) Naota, T.; Tannna, A.; Murahashi, S.-I. J. Am. Chem. Soc. 2000,
122, 2960.
Runsink, J.; Boche, G.; Marsch, M.; Ahlbrecht, H.; Sommer, H. Eur.
J. Org. Chem. 1998, 63. (b) Kawakami, Y.; Hisada, H.; Yamashita, Y.
Tetrahedron Lett. 1985, 26, 5835. (c) Watt, D. S. Synth. Commun. 1974,
(9) (a) Henderson, K. W.; Kennedy, A. R.; MacDougall, D. J.; Shanks,
D. Organometallics 2002, 21, 606. (b) Barker, J.; Barnett, N. D. R.;
Barr, D.; Clegg, W.; Mulvey, R. E.; O’Neil, P. A. Angew. Chem., Int.
Ed. Engl. 1993, 32, 1366.
4
1
, 127. (d) Kruger, C. R.; Rochow, E. G. Angew. Chem., Int. Ed. Engl.
963, 2, 617. (e) Prober, M. J. Am. Chem. Soc. 1956, 78, 2274.
(
4) Fleming, F. F.; Zhang, Z. Tetrahedron 2005, 61, 747.
5) Boche, G. Angew. Chem., Int. Ed. Engl. 1989, 28, 277.
(10) Lithiated cyclopropanenitrile 2 is unique in having N- and
C-coordination.
(
1
0.1021/jo0501184 CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/14/2005
J. Org. Chem. 2005, 70, 3845-3849
3845

Fleming et al.
quency.11 This coordination promiscuity is encapsulated
in the thermally induced interconversion of the N- and
C-phenylsulfonylacetonitriles 3 and 4 (Figure 1).12
Extensive NMR analyses of the metalated nitriles
identify the predominant solution structures as being
propargyl bromide causes exclusive S
2 displacement,
N
whereas conversion to the C-metalated nitrile 11 and
N
alkylation with propargyl bromide gives the S 2′ alle-
nylnitrile 12 exclusively (Scheme 1).21 Related regiodi-
vergent alkylations in polar and nonpolar solvents may
result from analogous preferential formation of N- or
13
essentially identical to those observed in the solid state.
6
15
22
Li- N NMR coupling confirms the preference for the
C-metalated nitriles.
N-lithiated dimer 1 in ether-toluene solvent mixtures,14
whereas the transition-metal-containing nitriles 3 and
SCHEME 1. Divergent Alkylations of N- and
C-Metalated Nitriles
13
4
exhibit solution- C chemical shifts for the nitrile
carbon, indicative of the corresponding N- and C-meta-
15
lated nitriles (δ ) 140-155 and 110-125, respectively).
Diagnostic C NMR shifts for the nitrile carbons of 5
1
3
16
1
7
and 6, which are only slightly shifted from those of the
parent neutral nitriles similarly suggest C-metalated
nitrile solution structures (Figure 2). Resident within this
continuum of N- and C-metalated nitriles is the com-
plexed lithioacetonitrile (7), which exists as a rapidly
equilibrating mixture of N- and C-coordinated nitriles in
ether at -100 °C.18
Even more intriguing are stereodivergent alkylations
of N- and C-metalated nitriles that are subtly inferred
from stereoselectivity trends in cyclopropanecarbonitrile
deuterations,23 solvent-selective cyclizations to cis- and
24
trans-decalins, and alkylations of cylohexanecarboni-
4
triles. The modest selectivity for the deprotonation-
methylation of the conformationally locked nitrile 13 and
the completely stereoselective methylation of the corre-
sponding magnesiated nitrile similarly imply selective
formation of N- and C-metalated nitrile intermediates
(
Scheme 2).25 The potential for complementary stereose-
FIGURE 2. Solution structures of metalated nitriles.
lectivities in alkylations of N- and C-metalated nitriles
stimulated a comprehensive series of alkylations. Alky-
Several intriguing alkylations with metalated nitriles
imply that the metal coordination site profoundly influ-
(
12) For an analogous interconversion of palladium complexes see:
19
ences the reactivity of metalated nitriles. For example,
Kujime, M.; Hikichi, S.; Akita, M. Organometallics 2001, 20, 4049.
(13) Abbotto, A.; Bradamante, S.; Pagani, G. A. J. Org. Chem. 1993,
intercepting the putative1
4,20
N-lithiated nitrile 9 with
5
8, 449.
(
1994, 116, 11602.
(15) Naota, T.; Tannna, A.; Murahashi, S.-I. Chem. Commun. 2001,
63.
14) Carlier, P. R.; Lucht, B. L.; Collum, D. B. J. Am. Chem. Soc.
(
11) For C-metalated nitriles see: (a) Naota, T.; Tannna, A.;
Kamuro, S.; Murahashi, S.-I. J. Am. Chem. Soc. 2002, 124, 6842. (b)
Naota, T.; Tannna, A.; Murahashi, S.-I. J. Am. Chem. Soc. 2000, 122,
2
960. (c) Alburquerque, P. R.; Pinhas, A. R.; Krause Bauer, J. A. Inorg.
(16) (a) Thibonnet, J.; Vu, V. A.; Berillon, L.; Knochel, P. Tetrahe-
dron, 2002, 58, 4787. (b) Thibonnet, J.; Knochel, P. Tetrahedron Lett.,
2000, 41, 3319.
(17) (a) Orsini, F. Synthesis 1985, 500. See also (b) Goasdoue, N.;
Gaudemar, M. J. Organomet. Chem. 1972, 39, 17.
(18) Sott, R.; Granander, J.; Hilmersson, G. J. Am. Chem. Soc. 2004,
126, 6798.
(19) (a) Fleming, F. F.; Zhang, Z.; Wei, G.; Steward, O. W. Org. Lett.
2005, 7, 447. (b) Caron, S.; Vazquez, E.; Wojcik, J. M. J. Am. Chem.
Soc. 2000, 122, 712. (c) Wu, Y.-D.; Houk, K. N.; Florez, J.; Trost, B. M.
J. Org. Chem. 1991, 56, 3656. (d) Leung, C.-S.; Rowlands, M. G.;
Jarman, M.; Foster, A. B.; Griggs, L. J.; Wilman, D. E. V. J. Med. Chem.
1987, 30, 1550. (e) Trost, B. M.; Florez, J.; Jebaratnam, D. J. J. Am.
Chem. Soc. 1987, 109, 613.
(20) Carlier, P. R.; Lo, C. W.-S. J. Am. Chem. Soc. 2000, 122, 12819.
(21) Fleming, F. F.; Zhang, Z.; Liu, W.; Knochel, P. J. Org. Chem.
2005, 70, 2200.
Chim. Acta 2000, 298, 239. (d) Ruiz, J.; Rodr ´ı guez, V.; L o´ pez, G.;
Casab o´ , J.; Molins, E.; Miravitlles, C. Organometallics 1999, 18, 1177.
(
1
e) Ragaini, F.; Porta, F.; Fumagalli, A.; Demartin, F. Organometallics
991, 10, 3785. (f) Porta, F.; Ragaini, F.; Cenini, S.; Demartin, F.
Organometallics 1990, 9, 929. (g) Ko, J. J.; Bockman, T. M.; Kochi, J.
K. Organometallics 1990, 9, 1833. (h) Cowan, R. L.; Trogler, W. J. Am.
Chem. Soc. 1989, 111, 4750. (i) Del Pra, A.; Forsellini, E.; Bombieri,
G.; Michelin, R. A.; Ros, R. J. Chem. Soc., Dalton Trans. 1979, 1862.
(
j) Lenarda, M.; Pahor, N. B.; Calligaris, M.; Graziani, M.; Randaccio,
L. J. Chem. Soc., Chem. Commun. 1978, 279. (k) Schlodder, R.; Ibers,
J. A.; Lenarda, M.; Graziani, M. J. Am. Chem. Soc. 1974, 96, 6893. (l)
Yarrow, D. J.; Ibers, J. A.; Lenarda, M.; Graziani, M. J. Organomet.
Chem. 1974, 70, 133. For N-metalated nitriles see: (a) Tanabe, Y.;
Seino, H.; Ishii, Y.; Hidai, M. J. Am. Chem. Soc. 2000, 122, 1690. (b)
Murahashi, S.-I.; Take, K.; Naota, T.; Takaya, H. Synlett 2000, 1016-
1
018. (c) Triki, S.; Pala, J. S.; Decoster, M.; Molini e´ , P.; Toupet, L.
Angew. Chem., Int. Ed. 1999, 38, 113. (d) Hirano, M.; Takenaka, A.;
Mizuho, Y.; Hiraoka, M.; Komiya, S. J. Chem. Soc., Dalton Trans. 1999,
(22) (a) Sommer, M. B.; Begtrup, M.; Bøgesø, K. P. J. Org. Chem.
1990, 55, 4817. (b) For computed structural differences in the extent
of C- and N-coordination for lithiated, sodiated, and magnesiated
acetonitrile see: Kaneti, J.; Schleyer, P. V. R.; Clark, T.; Kos, A. J.;
Spitznagel, G. W.; Andrade, J. G.; Moffat, J. B. J. Am. Chem. Soc. 1986,
108, 1481.
3
209. (e) Yates, M. L.; Arif, A. M.; Manson, J. L.; Kalm, B. A.; Burkhart,
B. M.; Miller, J. S. Inorg. Chem. 1998, 37, 840. (f) J a¨ ger, L.; Tretner,
C.; Hartung, H.; Biedermann, M. Chem. Ber. 1997, 130, 1007. (g) Zhao,
H.; Heintz, R. A.; Dunbar, K. R. J. Am. Chem. Soc. 1996, 118, 12844.
(
h) Murahashi, S.-I.; Naota, T.; Taki, H.; Mizuno, M.; Takaya, H.;
(23) Walborsky, H. M.; Motes, J. M. J. Am. Chem. Soc. 1970, 92,
2445.
Komiya, S.; Mizuho, Y.; Oyasato, N.; Hiraoka, M.; Hirano, M.;
Fukuoka, A. J. Am. Chem. Soc. 1995, 117, 12436. (i) Hirano, M.; Ito,
Y.; Hirai, M.; Fukuoka, A.; Komiya, S. Chem. Lett. 1993, 2057. (j)
Mizuho, Y.; Kasuga, N.; Komiya, S. Chem. Lett. 1991, 2127. (k)
Schlodder, R.; Ibers, J. A. Inorg. Chem. Soc. 1974, 13, 2870. (l) Ricci,
J. S.; Ibers, J. A. J. Am. Chem. Soc. 1971, 93, 2391.
(24) Fleming, F. F.; Shook, B. C. J. Org. Chem. 2002, 67, 2885. See
also: Trost, B. M.; Florez, J.; Jebaratnam, D. J. J. Am. Chem. Soc.
1987, 109, 613.
(25) For a preliminary communication see: Fleming, F. F.; Zhang,
Z.; Knochel, P. Org. Lett. 2004, 6, 501.
3846 J. Org. Chem., Vol. 70, No. 10, 2005

Cyclic Nitriles: Diastereoselective Alkylations
SCHEME 2. Stereoselective Methylations of
Metalated Nitriles
TABLE 1. LiNEt2 Deprotonation-Alkylation of
-tert-Butylcyclohexanecarbonitrile
4
lations with a conformationally constrained N-lithiated
nitrile were probed to establish the fundamental depen-
dence of the solvent, the temperature, and the electro-
phile on the stereoselectivity and to allow subsequent
comparison with C-metalated nitriles having magnesium
and copper counterions. Collectively, modest stereose-
lectivities correlate with sterically controlled alkylations
of N-lithiated nitriles, whereas the corresponding C-
metalated nitriles alkylate with high selectivities.
Results and Discussion
Pioneering26 isotope labeling identified an early transi-
tion state for alkylations of lithiated 4-tert-butylcyclo-
hexanecarbonitrile. Deprotonating 13 with lithium di-
ethylamide in DME is presumed to generate a planar
N-lithiated nitrile27 with only a slight steric bias for an
electrophile approach along an equatorial trajectory
a
1
Ratios determined by 500 MHz H NMR integration of the
2
9 b
Reference 29c. c Reference
axial and equatorial diastereomers.
26. Repetition under the original conditions afforded a 3.6:1 ratio
85%), which compares favorably with the methylation ratio (3.1:
) of the corresponding lithiated nitrile generated by fragmentation
of a methyldiazine carboxylate.
(
1
30
(
Table 1, entry 6).28 Repeating the benchmark deproto-
SCHEME 3. Stereoselective Alkylations of an
N-Lithiated Nitrile
nation-methylation of nitrile 13 in THF, DME, and
toluene at varying temperatures and with different
electrophiles (Table 1) provides a crucial reference point
for comparing the stereoselective alkylations of diverse
metalated nitriles. Not surprisingly, the stereoselectivity
is virtually identical in THF and DME, with modestly
improved selectivity at low temperatures and minimal
selectivity at or above room temperature (Table 1,
compare entries 6 and 7 with entries 3 and 4 and entries
8
-10, respectively).
Alkylations of 13 are consistent with the formation of
a planar N-lithiated nitrile20 (17) upon deprotonation
(Scheme 3). Specifically, the planar lithiated nitrile 17
exhibits a 2.8:1 preference for equatorial methylation at
room temperature, which is very similar to the methy-
lation selectivities of the planar enolates 18a, 18b, and
phile, methyl iodide (Table 1, compare entries 5 and 6).
Comparative alkylations of allyl- and propyl bromide,
having virtually identical steric demands, are completely
stereoselective in the latter case, presumably reflecting
better steric discrimination from the less-reactive elec-
trophile in a later transition state (Table 1, compare
entries 1 and 2).
3
1
31
28
1
8c (1.8:1, 5.3:1, and 5.7:1, respectively). An axial
electrophile trajectory to the nucleophilic orbital of 17 is
modestly disfavored by 1,3-syn-axial interactions,32 which
are exacerbated by sterically demanding electrophiles.33
For example, alkylations with allyl bromide are modestly
more selective than alkylations with the smaller electro-
Alkylations of copper- and magnesium-derived meta-
lated nitriles exhibit dramatically improved stereoselec-
tivities. Metalated nitriles having different metal cations
(
26) Bare, T. H.; Hershey, N. D.; House, H. O.; Swain, C. G. J. Org.
Chem. 1972, 37, 997.
27) For leading references see: (a) Corset, J.; Castell a` -Ventura, M.;
Froment, F.; Strzalko, T.; Wartski, L. J. Org. Chem. 2003, 68, 3902.
3
4
are readily generated by halogen-metal exchange of
(
(32) For general discussions see: (a) reference 4. (b) Frater, G.
Alkylation of Ester Enolates. In Stereoselective Synthesis; Helmchen,
G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds. Houben-Weyl:
New York, 1996; Vol. 2, pp 723-790. (c) Caine, D. Alkylations of Enols
and Enolates. In Comprehensive Organic Synthesis; Trost, B. M.;
Fleming, I., Eds.; Oxford: Pergamon: 1991; Vol. 3, pp 1-63. (d) Evans,
D. A. In Asymmetric Synthesis Morrison, J. D., Ed.; Academic Press:
New York, 1984; Vol. 3, Chapter 1.
(
b) Reference 20.
(
28) House, H. O.; Bare, T. M. J. Org. Chem. 1968, 33, 943.
28,a
b
(
29) The stereochemical assignments for 14a/15a
and 14c/15c
1
3
are based on C NMR shift comparisons with known values, whereas
13
the stereochemistry of 15b rests on the diagnostic C NMR shift for
a
the axial nitrile group (δCN 124.4, 123.7, 123.2 for 14a-c, respectively).
(
a) Bailey, W.; Cioffi, A. Magn. Reson. Chem. 1987, 25, 181. (b) House,
H. O.; Lubinkowski, J.; Good, J. J. J. Org. Chem. 1975, 40, 86.
(33) Alkylation with sterically demanding iodomethyltributylstan-
nane occurs exclusively from the equatorial direction: Pearlman, B.
A.; Putt, S. R.; Fleming, J. A. J. Org. Chem. 1985, 50, 3625.
(
30) Ziegler, F. E.; Wender, P. A. J. Org. Chem. 1977, 42, 2001.
31) Krapcho, A. P.; Dundulis, E. A. J. Org. Chem. 1980, 45, 3236.
(
J. Org. Chem, Vol. 70, No. 10, 2005 3847

Fleming et al.
TABLE 2. Diastereoselective Halogen-Metal Exchange
SCHEME 4. Equilibration of C-Metalated Nitriles
Alkylations
comparable i-PrMgBr exchange alkylations (Table 2,
compare entries 8 and 9 with entries 5-7). The highly
selective alkylations with i-PrMgBr and Me CuLi directly
2
contrast with the BuLi exchange methylation, in which
the modest selectivity (Table 2, entry 1) more closely
parallels the deprotonation-methylation of 13 with Li-
2
NEt (Table 1).
The divergent alkylation stereoselectivities of meta-
lated nitriles with magnesium and copper counterions,
as opposed to lithium, require the formation of distinctly
different metalated nitriles (compare, in particular, Table
2
, entry 4 with Table 1, entry 7 and Table 2, entry 8 with
37
Table 1, entry 2). Identifying the lithiated nitrile as a
planar N-lithiated nitrile structure (Table 1 and Table
2
, entry 1) is consistent with the prior alkylation prefer-
2
8,31
14
ences of planar enolates
and NMR and X-ray
a
A diastereomeric mixture of bromonitriles was employed
structural studies,5 suggesting that magnesium and
unless otherwise specified. Ratios are based on isolated yields of
b
copper counterions preferentially form C-metalated ni-
triles. Mechanistically, addition of i-PrMgBr or Me CuLi
2
diastereomeric nitriles. A single diastereomeric bromonitrile was
employed. c The stereochemistry of 14d was assigned by reduction
3
6 d
and X-ray crystallography of the corresponding alcohol (i).
A
to the bromonitrile 16 is presumed to generate the
single bromonitrile diastereomeric to that in entry 6 was employed.
38
bromate 19 (Scheme 4) that fragments to directly
generate the C-metalated nitriles 20 or 22 or the corre-
3
9
sponding N-metalated nitrile 21. In either case, rapid
the corresponding bromonitriles,21 which, in the case of
40
conducted tour equilibration to one predominant meta-
lated nitrile is consistent with the qualitatively identical
ratios of acylated nitriles 14d and 15d (Table 2, entries
1
3
6, is readily prepared by bromination of 13 with PBr ,
2
3
5
41
Br
(eq 1). Exploratory bromine-magnesium exchange
in the presence of methyl iodide affords the equatorially
6 and 7) upon addition of i-PrMgBr to a -78 °C, THF
solution containing methyl cyanoformate and diastereo-
merically pure cis- or trans-bromonitrile 16. Similarly,
probing the configurational stability through the in situ
methylation of a 1-2:1 diastereomeric mixture of bro-
monitriles 16 leads exclusively to the equatorially me-
thylated nitrile 14a (Table 2, entries 2-4).
methylated nitrile 14a as the sole diastereomer (Table
2
, entry 2), which is in direct contrast to comparable
(
36)
methylations of the corresponding lithiated nitrile (Table
, entry 1 and Table 1, entry 4). Probing the effect of
2
temperature on the magnesium exchange methylation
proved to be particularly revealing. Remarkably, the
exclusive preference for equatorial methylation is main-
tained for i-PrMgBr exchange alkylations at 0 °C and at
room temperature, which is in direct contrast to lithium
diethylamide deprotonation methylations (compare Table
The supplementary crystallographic data for i, CCDC no. 259789,
can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retriev-
ing.html or from the Cambridge Crystallographic Data Center, 12
Union Road, Cambridge CB2 1EZ, UK (fax +44 1223 336033; or
deposit@ccdc.cam.ac.uk.).
(
37) Attempts to access the magnesiated nitrile 22 (MX ) MgBr)
2
, entries 2-4 with Table 1, entries 4 and 7). Analogous
by deprotonating 13 with BrMgNEt
2
afforded the corresponding
i-PrMgBr exchange alkylations with more reactive elec-
trophiles, such as allyl bromide and methyl cyanoformate,
selectively generate the corresponding equatorially alky-
lated nitriles (Table 2, entries 5-7). Sequential bromine-
copper exchange and alkylation with allyl bromide or
methyl cyanoformate is even more selective than the
amidine.
(38) (a) Hoffmann, R. W.; Br o¨ nstrup, M.; Muller, M. Org. Lett. 2003,
5
, 313. (b) Schulze, V.; Br o¨ nstrup, M.; B o¨ hm, V. P. W.; Schwerdtfeger,
P.; Schimeczek, M.; Hoffmann, R. W. Angew. Chem., Int. Ed. 1998,
3
7, 824. (c) Reich, H. J.; Green, D. P.; Phillips, N. H.; Borst, J. P.; Reich,
I. L. Phosphorus, Sulfur Silicon Relat. Elem. 1992, 67, 83.
39) For a related equilibration see: Reich, H. J.; Medina, M. A.;
Bowe, M. D. J. Am. Chem. Soc. 1992, 114, 11003.
(
(
40) Carlier, P. R. Chirality 2003, 15, 340.
(
34) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp,
(41) The ratios of 14b and 15b were essentially identical as
1
F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003,
determined by integration of the crude H NMR spectra. The variable
4
2, 4303.
ratios observed in Table 2, entries 6 and 7, most likely reflect the small
quantities isolated for the minor isomer.
(35) Stevens, C. L.; Coffield, T. H. J. Am. Chem. Soc. 1951, 73, 103.
3848 J. Org. Chem., Vol. 70, No. 10, 2005

Cyclic Nitriles: Diastereoselective Alkylations
The high, or exclusive, equatorial alkylation prefer-
ences with magnesium and copper counterions are con-
sistent with the retentive alkylation42 of equatorial
C-metalated nitriles (22, Scheme 4). The exceptionally
small steric demand of the nitrile group, a mere 0.2 kcal
mol, is anticipated to favor diastereomer 22 over 20, in
which the larger, solvated metal adopts the axial orienta-
tion. Detecting the minor conformer 20 through alkyla-
tion is facilitated with particularly reactive electrophiles44
and may account for the formation of trace acylated and
allylated nitriles 15c and 15d in alkylations with allyl
bromide and methyl cyanoformate (Table 2, entries 5-7).
As expected, the less-reactive cuprated nitrile exhibits
greater discrimination in alkylations with allyl bromide
and methyl cyanoformate (compare Table 2, entries 5-7
with entries 8 and 9).
stereoselectivity preferences. Alkylations of N-lithiated
nitriles, generated by lithium diethylamide deprotonation
or bromine-lithium exchange, exhibit a modest sterically
controlled preference for equatorial alkylation. Sequential
bromine-magnesium or bromine-copper exchange alky-
lations are consistent with the formation of equatorial
C-metalated nitriles, which exhibit a high, or exclusive,
preference for retentive alkylation. Selectively forming
N- or C-metalated nitriles provides complementary ste-
reocontrol manifolds for overcoming the long-standing
difficulty of achieving highly selective alkylations with
sterically unbiased cyclohexanecarbonitriles.
4
3
Acknowledgment. Financial support of this re-
search, and for X-ray equipment, from NSF is gratefully
acknowledged, as are insightful discussions with Dr.
Paul Carlier.
Note Added after ASAP Publication. There was an
error in the structure numbers of reference 44 in the version
published ASAP April 14, 2005; the corrected version was
published ASAP April 18, 2005.
N- and C-metalated conformationally locked nitriles
alkylate electrophiles with divergent and diagnostic
(42) For an excellent overview see: Clayden, J. In Organolithiums:
Selectivity for Synthesis; Pergamon: Amsterdam, 2002; Chapter 6. For
retentive alkylation of a chiral organocopper reagent see: Hoffmann,
R. W.; H o¨ lzer, B. J. Am. Chem. Soc. 2002, 124, 4204.
Supporting Information Available: Experimental pro-
1
13
cedures, H NMR, and C NMR spectra for all new com-
pounds, and an ORTEP for i. This material is available free
of charge via the Internet at http://pubs.acs.org.
(43) Eliel, E. L.; Wilen, S. H.; Mander, L. N. In Stereochemistry of
Organic Compounds; Wiley: NY, 1994; pp 696-697.
44) The analysis assumes similar reactivities of the transition states
for alkylations of 20 and 22, which may be a reasonable assumption
(
26
given the early transition state for alkylations of N-lithiated nitriles.
JO0501184
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