Transition Structure Geometries for Transfers of Neutral and Anionic Nitrogen to Lithiated Carbanions

Article abstract of DOI:10.1021/jo990509g

The geometries of nucleophilic substitutions at neutral and anionic nitrogen by organolithium species have been investigated. The demonstration of an intramolecular conversion of 9 to 10 provides an endocyclic restriction test which supports a trigonal bipyramidal transition structure for nitrogen transfer. A lack of isotopic scrambling of 12a-¹⁸O during nitrogen transfer is taken to rule out reaction via an oriented ion pair. Attempted endocyclic restriction tests for transfers of formally anionic nitrogen with 32 and 33 were not successful. Reactions of n-butyl, s-butyl and tert-butyllithium reagents with 16, 23, 30, 31, and 36-38 generally afford higher yields with increasing substitution at the carbon of the organolithium reagent and with decreasing substitution adjacent to the nitrogen of the aminating reagent. These results are consistent with trigonal bipyramidal transition states for nucleophilic displacements of oxygen by carbon at neutral and anionic nitrogen.

Full text of DOI:10.1021/jo990509g

5218
J . Org. Chem. 1999, 64, 5218-5223
Tr a n sition Str u ctu r e Geom etr ies for Tr a n sfer s of Neu tr a l a n d
An ion ic Nitr ogen to Lith ia ted Ca r ba n ion s
Peter Beak,* Kathryn Conser Basu, and J ames J . Li
Department of Chemistry, University of Illinois, Urbana, Illinois 61801
Received March 23, 1999
The geometries of nucleophilic substitutions at neutral and anionic nitrogen by organolithium species
have been investigated. The demonstration of an intramolecular conversion of 9 to 10 provides an
endocyclic restriction test which supports a trigonal bipyramidal transition structure for nitrogen
transfer. A lack of isotopic scrambling of 12a -18O during nitrogen transfer is taken to rule out
reaction via an oriented ion pair. Attempted endocyclic restriction tests for transfers of formally
anionic nitrogen with 32 and 33 were not successful. Reactions of n-butyl, s-butyl and tert-
butyllithium reagents with 16, 23, 30, 31, and 36-38 generally afford higher yields with increasing
substitution at the carbon of the organolithium reagent and with decreasing substitution adjacent
to the nitrogen of the aminating reagent. These results are consistent with trigonal bipyramidal
transition states for nucleophilic displacements of oxygen by carbon at neutral and anionic nitrogen.
In tr od u ction
classic SN2 substitution. An alternative pathway could
involve initial bond cleavage to generate an intermediate,
shown as the nitrenum ion,4 which would react with a
nucleophile in a second step. If the aminating reagent
was an alkoxyamide anion, the concerted pathway would
involve nucleophilic attack at a formally negative nitro-
gen while the stepwise process would proceed via a formal
nitrenoid.
Kinetic evidence has been interpreted to favor con-
certed pathway for most aminations.3 However kinetic
data support a stepwise pathway for reactions in which
an intermediate nitrenium ion can be stabilized by an
aromatic ring.5 The difference between the restricted
geometry required by a trigonal bipyramidal transition
structure, and the less constrained geometry of a dis-
sociative pathway has been probed for aminations of
lithiated carbanions by the endocyclic restriction test.6
Those experiments revealed that displacements at both
neutral and anionic nitrogen in small and medium-sized
rings are intermolecular, consistent with the classic SN2
pathway.7 Theoretical calculations are also consistent
with this interpretation.2
Aminative processes which can be represented as
nucleophilic displacements at nitrogen are reactions of
mechanistic, synthetic, biochemical, and theoretical
interest.1-4 The limiting mechanisms for transfer of
nitrogen from bonding to a leaving group to bonding to a
first row nucleophile are illustrated by the conversion of
1 to 2. In the concerted pathway bond making and bond
breaking would occur simultaneously via 3. This transi-
tion structure is shown as the trigonal bipyramid of a
We now report investigations of transfers of nitrogen
from oxygen to carbanions which could take place within
large endocyclic rings. We also report studies of the effect
of substitution on these nucleophilic displacements.
(1) For reviews of electrophilic aminating reagents, see: Boche, G.
Houben-Weyl, Methods of Organic Chemistry, Vol. E21e; Helmchen,
G., Hoffmann, R. W., Mulzer, J ., Eds.; Schauman, Thieme: Stuttgart,
1995; p 5133. Erdik, E.; Ay, M. Chem. Rev. 1989, 89, 1947. Mulzer, J .;
Altenbach, H.-J .; Braun, M.; Krohn, K.; Reissig, H.-U. Organic
Synthesis Highlights: VCH Publishers: Weinheim, 1991; p 45. Greck,
C.; Geneˆt, J . P. Syn. Lett. 1977, 741.
Resu lts a n d Discu ssion
Rea ction s a t Neu tr a l Nitr ogen . En d ocyclic Re-
str iction Test in a La r ge Rin g. We have previously
(2) McKee, J . J . Am. Chem. Soc. 1985, 107, 859. Armstrong, D. R.;
Snaith, R.; Walker, G. T. J . Chem. Soc., Chem. Commun. 1985, 789.
Boche, G.; Wagner, H.-U. J . Chem. Soc., Chem. Commun. 1984, 1591.
Cramer, C. J .; Dulles, F. J .; Falvey, D. E. J . Am. Chem. Soc. 1994,
116, 9787. Bu¨hl, M.; Schaefer, H. F., III J . Am. Chem. Soc. 1993, 115,
9143. Bu¨hl, M.; Schaefer, H. F., III J . Am. Chem. Soc. 1993, 115, 364.
Glukhovtseu, M. N.; Pross, A.; Radam, L.; J . Am. Chem. Soc., 1995,
117, 9012.
(3) Helmick, J . S.; Martin, K. A.; Heinrich, J . L.; Novak, M. J . Am.
Chem. Soc. 1991, 113, 3549. Ulbrich, R.; Famulok, M.; Bosold, F.;
Boche, G. Tetrahedron Lett. 1990, 31, 1689. Campbell, J . J .; Glover,
S. A. J . Chem. Soc., Perkin Trans. 2 1992, 1661.
(5) Novak, M.; Kennedy, S. A. J . Am. Chem. Soc. 1995, 117, 574.
Davidse, P. A.; Kahley, M. J .; McClelland, R. A.; Novak, M. J . Am.
Chem. Soc. 1994, 116, 4513. Novak, M.; Kahley, M. J .; Lin, J .; Kennedy,
S. A.; Swanegan, L. A. Am. Chem. Soc. 1994, 116, 11626. Defrancq,
E.; Pelloux, N.; Leterne, A.; Lhomme, M.-F.; Lhomme, J . J . Org. Chem.
1991, 56, 4817. Robbins, R. J .; Laman, D. M.; Falvey, D. E. J . Am.
Chem. Soc. 1996, 118, 8127.
(6) For a review of the endocyclic restriction test, see: Beak, P. Acc.
Chem. Res. 1992, 25, 215.
(7) (a) Beak, P.; Basha, A.; Kokko, B. J . Am. Chem. Soc. 1984, 106,
1511. (b) Beak, P.; Basha, A.; Kokko, B. J .; Loo, D. J . Am. Chem. Soc.
1986, 108, 6016. (c) Beak, P.; Selling, G. W. J . Org. Chem. 1989, 54,
5574. (d) Beak, P.; Li, J . J . Am. Chem. Soc. 1991, 113, 2796.
(4) For discussions of aminations related to carcinogenesis, see:
Singer, B.; Kusmierek, J . T. Annu. Rev. Biochem. 1982, 51, 655. Lai,
C. C.; Miller, E. C.; Miller, J . A.; Leim, A. Carcinogenesis 1987, 8, 471.
10.1021/jo990509g CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/24/1999

Transition Structure Geometries
J . Org. Chem., Vol. 64, No. 14, 1999 5219
communicated our observation that the conversion of 5
to 6 is an intermolecular reaction based on double
labeling of 5 and isotopic analysis which reveals isotopic
scrambling in 6.7d,8 The inference from this endocyclic
restriction test is that a large bond angle is required for
nucleophilic displacement at nitrogen and the reaction
proceeds via a trigonal bipyramidal transition structure.9
The synthesis of 9 was carried out in a eight-step
sequence from readily available starting materials as
shown in Scheme 1. The reactions in the scheme were
straightforward except for the coupling reaction between
the aryl iodide and dimethyl phenylphosphonite. Nickel
chloride was not an effective catalyst, but with palladium
acetate or palladium chloride as the catalyst, the reaction
proceeded smoothly and provided the desired product in
82% yield.10 The identity of 9 was established by spec-
troscopic data and elemental analysis. The doubly labeled
compound 9-2H,13C was prepared following the same
procedure as for 9 using K13CN (13C ) 99%) and HONCH3-
CH22H (2H ) 97%) to incorporate the isotopic labels.
The authentic amination product 10 was also prepared
from the reaction of 11 with 12 as shown in Scheme 2.
If we use effective molarity values of 0.01-0.05 for
cyclization of a 16-membered ring, an intramolecular
endocyclic reaction of 9 to give 10 should be accessible
at ca. 0.001 M.11 Using LDA, the benzylic carbanion 7
was generated from 9 at a concentration of 0.001 M.
Workup of the reaction followed by reaction with diazo-
methane gave the substitution product 10 in 7% yield.
To determine the molecularity of the conversion of 9
to 10, a double-labeling experiment was carried out with
a ca. 1:1 mixture of unlabeled 9 and doubly labeled
9-2H13C. The product 10 was obtained in ca. 10% yield.
The isotopic distribution of the mixture of 10 and 10-
2H13C was determined by FABMS analysis and compared
to the isotopic distribution of the reactant mixture of 9
and 9-2H13C. The reactant isotopic composition was based
on the weight of the unlabeled 9 and doubly labeled
reactant 9-2H13C.12
When a ring is of sufficient size to allow both the
entering and leaving groups to be simultaneously apical
in a trigonal bipyramidal transition structure, an in-
tramolecular endocyclic reaction would be expected. We
have carried out this study in a prospective 16-membered
endocyclic ring for the conversion of 7 to 8 by investiga-
tion of the conversion of 9 to 10.
(9) Discussion of these results and the experimental details are
provided as supporting materials. See also: J . Li or K. Conser Ph.D.
Thesis deposited with Michigan Microfilms Inc., Ann Arbor, MI.
(10) The use of nickel chloride as a catalyst to carry out this type of
coupling reaction was first reported by Tavs and modified by Miles,
Grabiak and Cummins, see: Tavs, P. Chem. Ber. 1970, 103, 2428.
Miles, J . A.; Grabiak, R. C.; Cummins, C. J . Org. Chem. 1982, 47, 1677.
(11) Galli, C.; Illuminati, G.; Mandolini, L.; Tamborra, P. J . Am.
Chem. Soc. 1977, 99, 2591. Illuminati, G.; Mandolini, L.; Masci, B. J .
Am. Chem. Soc. 1977, 99, 6308. Casadei, M. A.; Galli, C.; Mandolini,
L. J . Am. Chem. Soc. 1984, 106, 1051.
(8) For the use of the phosphinyl function to activate oxygen as a
leaving group from nitrogen, see: (a) Boche, G.; Bernheim, M.; Schrott,
W. Tetrahedron Lett. 1982, 5399. (b) Colvin, E. W.; Kirby, G. W.;
Wilson, A. C. Tetrahedron Lett. 1982, 3835. (c) Ulbrich, R.; Famulok,
M.; Bosold, F.; Boche, G. Tetrahedron Lett. 1990, 1689.

5220 J . Org. Chem., Vol. 64, No. 14, 1999
Beak et al.
Sch em e 1
Sch em e 2
If the reaction proceeded by an intramolecular process,
the product would be a mixture of 10 and 10-2H13C with
the same isotopic distribution as that of the reactant
mixture of 9 and 9-2H13C. If the reaction proceeded by
an intermolecular pathway, the products would be 10,
10-13C, 10-2H, and 10-2H13C with a statistical distribution
of the isotope. From the composition of the reactant
mixture of 9 and 9-2H13C, the isotopic compositions of 10
which would be expected for intramolecular and inter-
molecular processes are shown in Table 1, along with the
experimentally determined values for two experiments.
Comparison of the experimental values of the isotopic
distribution to the calculated values show that the
conversion of 7 to 8 occurs by an intramolecular pathway.
The double-labeling experiments with 5 and 9 establish
that there is a requirement for a large bond angle
between the entering and leaving group in these nucleo-
philic substitutions at neutral nitrogen.
mediate. An oriented ion pair, formed by a dissociation
in which the leaving group shields the front side of the
nitrogen from reaction with the nucleophile, could be
envisioned. In an effort to detect an ion pair in the
transfer of nitrogen from 12 to the anion of benzylcyanide
13 to give 14, we have carried out an oxygen-18 labeling
experiment.
Test for a n Ion P a ir . The demonstration that there
is a geometrical dependence for substitution at neutral
nitrogen does not definitively rule out a reaction inter-
(12) We were unable to directly measure the isotopic ratio of the
reactant mixture, because a molecular ion was not observed by FIMS
(M+) or FABMS (M + H)+. Only the corresponding phosphinic acid
was detected.

Transition Structure Geometries
J . Org. Chem., Vol. 64, No. 14, 1999 5221
Ta ble 1. Com p a r ison of Isotop ic Distr ibu tion of th e
Con ver sion of 9 to 10 for th e Dou ble-La belin g
Exp er im en ts
in the initial reactant. These data establishes that oxygen
scrambling did not occur during the course of the
substitution at nitrogen of 12a -18O. We take these results
to rule out the dissociative nitrenium ion-pair pathway
for nitrogen transfer in the reactions of 5 and 9, as well
as of 12.
isotopic distribution (%)
2H12C and
2H13
40
C
1H13
2
C
1H12
57
C
initial reactanta 9 + 9-2H13
C
product mixture 10 + 10-2H13
intramolecular reactionb
intermolecular reactionb
experimental valuec
C
C
40
17
42
2
48
3
57
34
56
initial reactanta 9 + 9-2H13
C
53
2
45
product mixture 10 + 10-2H13
intramolecular reactionb
intermolecular reactionb
experimental valuec
53
29
52
2
50
6
45
21
42
Rea ction a t Neu tr a l Nitr ogen . Effects of Ster ic
Hin d r a n ce. We have found that the yields of substitu-
tion products in intermolecular displacements are de-
pendent on the structure of the organolithium reagent
and the O-alkyl dialkyl hydroxylamine.15 The reaction
of N,N-bis(3-phenylpropyl)-O-methylhydroxylamine (16)
with t-BuLi, s-BuLi, and n-BuLi in hexanes gave the
substitution products 17, 18, and 19 in 72, 47, and ca.
5% yields, respectively, along with low yields of the
elimination-addition products 20-22.16 In these reac-
tions, the more substituted the organolithium reagent the
higher the yield of product. A similar order was also
observed in a reaction of 16 with a 1:1 mixture of t-BuLi
and n-BuLi; only the substitution product 17, from the
reaction of t-BuLi, was obtained.
a
Based on the weights of reactants in the mixture of 9 +
9-2H13C. Based on the estimated isotopic distribution of the
b
reactant mixture. c Determined by FABMS ((5%).
Ta ble 2. Oxygen -18 Con ten t in Rea cta n t a n d Recover ed
12-18Oa
from reactant 12a -18
O
from recovered 12a -18
O
47
47
49
46
a
Determined by FIMS ((5%).
Substitution reactions at the nitrogen of 12 have been
shown to proceed with second-order kinetics by Boche
and co-workers.8c If the reaction of 13 with 12 is also a
second-order reaction and proceeds via a nitrenium ion
pair, the rate-determining step must be nucleophilic
attack by the carbanion nucleophile on the ion pair. In
that case, the ion pair from the reactant 12a -18O would
be expected to have a sufficient lifetime to undergo
isotopic scrambling by recombination to afford 12b-18O
with scrambling of the label.13
Aminations of the butyllithium reagents by N,N-bis-
(3-cyclohexyl-n-propyl)-O-methylhydroxylamine (23) were
also investigated. The substitution products 24 and 25
obtained with t-BuLi and s-BuLi in 45 and 9% yields,
respectively, were characterized by 1H and 13C NMR and
GC/MS. No substitution product was obtained from the
reaction of 23 with n-BuLi.
Treatment of 12 with 13, generated in situ from benzyl
cyanide with LDA, gave the substitution product 14 in
65% yield.14 Labeled material 12a -18O with 47% 18O, as
established by reaction of 12a -18O with phenyllithium
and analysis of the label in the triphenyl phosphine oxide
(15-18O) produced, was prepared. Reaction of 12a -18O
with 13 was carried out twice for different reaction times
to give 14 in 28 and 39% yields, respectively, with
recovery of 12-18O in 37 and 17% yields, respectively. The
oxygen-18 content in the Pd18O position of the recovered
12a -18O, was determined by mass spectrometric analysis
of 15-18O, obtained by reaction of the recovered 12-18O
with phenyllithium. As shown in Table 2 this material
was found to have 49 and 46% 18O, consistent with that
(15) For discussions of classic SN2 substitutions at carbon, see:
Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic
Chemistry, 3rd ed.; Harper and Row: New York, 1987; Chapter 4.
Streitwieser, A., J r. Solvolytic Displacement Reactions; McGraw-Hill:
New York, 1962; pp 2-92. Ingold, C. K. Structure and Mechanism in
Organic Chemistry, 2nd ed.; Cornell University: Ithaca, NY, 1969; pp
421-610. Andreae, S.; Schmitz, E. Synthesis 1991, 327. Carey, F. A.;
Sundberg, R. J . Advanced Organic Chemistry, 3rd ed.; Plenum Press:
New York, 1997; pp 284-296.
(16) The structural assignments to 19-22, 28, and 29 are provi-
sional and based on GC-MS data, which gave the molecular ions as
well as the characteristic R-cleavage at nitrogen. The latter five
products are presumably formed by elimination of methoxide to give
an imine, followed by addition of the organolithium reagent.17
(13) This type of oxygen scrambling process has been shown to be a
sensitive test for detection of the ion pair intermediates for carboxy-
lates, sulfonates, and phosphinate esters. Goering, H. L.; Levy, J . F.
J . Am. Chem. Soc. 1964, 86, 120. Goering, H. L.; Briody, R. G.;
Sandrock, G. J . Am. Chem. Soc. 1970, 92, 7401. Dietze, P. E.;
Wojciechowski, M. J . Am. Chem. Soc. 1990, 112, 5240. Givens, R. S.;
Matuszewski, B.; Athey, P. S.; Stoner, M. R. J . Am. Chem. Soc. 1990,
112, 6016.
(14) Harger, M. J . P. J . Chem. Soc., Chem. Commun. 1979, 768.
Boche, G.; Sommerlade, R. H. Tetrahedron 1986, 2703.

5222 J . Org. Chem., Vol. 64, No. 14, 1999
Beak et al.
The order of yields of substitution products could be
taken to be indicate single electron transfer (SET) is a
key step in the reaction. In a SET mechanism, transfer
of an electron from the organolithium reagent could give
a nitrogen radical anion, which could expel alkoxide to
provide a nitrogen radical. This radical could couple with
the residual alkyl radical formed from the organolithium.
We have attempted to detect the presence of a long-
lived nitrogen radical by investigation of the reaction of
26, a potential radical reporter system, with t-BuLi. This
approach is based on the work of Newcomb et al. who
established a rate of cyclization for an analogous radical
tempted reaction with ony a trace of substitution product
observed with t-BuLi. These results are taken to show
that substituents a to nitrogen inhibit the substitution
reactions of N,N-dialkyl-O-alkylhydroxylamines.
Rea ction s a t An ion ic Nitr ogen . An Attem p ted
En d ocyclic Restr iction Test in a La r ge Rin g. Nu-
cleophilic substitutions at formally anionic nitrogen have
been known since the work of Sheverdina and Kochesh-
kov.19 We have reported synthetic applications of such
aminations for N-alkyl-O-alkylhydroxylamines in exocy-
clic intramolecular modes to provide four to seven
membered rings.7 We have also shown that for N-alkyl-
O-alkyl hydroxylamines in which the reaction might
proceed in an endocyclic five, six, or seven-membered
ring, the nitrogen transfers are intermolecular.20
as 105s-1 18
Reaction of 26 with t-BuLi gave a 67% yield
.
of substitution product 27 and a ca. 5% mixture of 28
and 29.16 Since we did not detect any cyclized product
from 26, we did not obtain positive evidence for a long-
lived radical intermediate. However the cyclization of this
radical would be slow, and this result should not be taken
as definitive evidence against a radical pathway.18
We have attempted to carry out endocyclic restriction
tests for transfers of formally anionic nitrogen in rings
of sufficient size to accommodate the entering and leaving
groups in the apical positions of a trigonal bipyramid.
Syntheses of 32 and 33, as well as the acylated products
of nitrogen transfer, 34 and 35, respectively, were carried
out.9 Conversions of 32 and 33 to the corresponding
dilithio intermediates were effected under a wide variety
of conditions, and the reaction products were investi-
gated. As detailed in the Supporting Information, the
products which were identified showed cleavage of the
ON bond, but we were unable to detect any 34 or 35 from
these reactions.20 Hence we have been unable to observe
the intramolecular component of the endocyclic restric-
tion test for substitutions at anionic nitrogen.
To determine the effect of substitutions on the O-
alkylhydroxylamine, we have investigated the reactions
of 30 and 31 with t-BuLi and s-BuLi. Substantial
amounts of 30 and 31 were recovered from each at-
Rea ction a t An ion ic Nitr ogen . Effects of Su bsti-
tu tion . The effect of increasing substitution of the
carbanion on the yields of amination products was
evaluated by investigation of the reactions of 36, 37 and
38 with t-BuLi, s-BuLi, and n-BuLi. Reactions carried
out by initial treatment of 36 initially with MeLi at -78
°C, followed by addition of the BuLi and warming to -10
°C, gave the amine products, 39, 40, and 41 in 99, 60,
and 68% yields, respectively. Aminations of t-BuLi and
s-BuLi with 37 provided the amines 42 and 43 in 61 and
66% yields, respectively. Reaction of 37 with n-BuLi did
not afford a substitution product. Reaction of the more
substituted aminating reagent, N-(a-methyl)benzyl-O-
methylhydroxylamine (38), with t-BuLi and s-BuLi gave
the substitution products 44 and 45 in 30 and 35% yields
in reactions which required warming. The elimination-
addition products 46 and 47 were obtained in 7 and 25%
yields, respectively. For reaction of n-BuLi with 38, the
elimination-addition product 48 was the only product
observed.
(17) (a) Kokko, B. J .; Beak, P. Tetrahedron Lett. 1983, 561. (b) We
have found that when N-(3-phenylpropyl)-N-(2′-methoxyethyl)-O-meth-
ylhydroxylamine (i) reacts with t-BuLi and n-BuLi, the elimination
addition products ii and iii, are formed in yields of 77 and 82%,
respectively. One interpretation is that a complex induced proximity
effect is involved.21
(18) Newcomb, M.; Horner, J . H.; Shahin, H. Tetrahedron Lett. 1993,
34, 5523. Newcomb, M.; Curran, D. P. Acc. Chem. Res. 1988, 21, 206,
and references therein. Newcomb, M.; Glenn, A. G.; Manek, M. B. J .
Org. Chem. 1989, 54, 4603. Newcomb, M.; Sanchez, R. M.; Kaplan, J .
J . Am. Chem. Soc. 1987, 109, 1195. Walling, C.; Cooley, J . H.; Ponaras,
A. A.; Racah, E. J . J . Am. Chem. Soc. 1966, 88, 5361. Newcomb, M.;
Burchill, M. T.; Deeb, T. M. J . Am. Chem. Soc. 1988, 110, 6528.
Newcomb, M.; Deeb, T. M. J . Am. Chem. Soc. 1987, 109, 3163.
Newcomb, M.; Burchill, M. T. J . Am. Chem. Soc. 1983, 105, 7759.
(19) Sheverdina, N. I.; Kocheshkov, Z. J . Gen. Chem. USSR 1938,
8, 1825.
(20) Self-decomposition of N-lithioalkoxides has been noted hereto-
fore. (a) Beak, P.; Kokko, B. J . J . Am. Chem. Soc. 1982, 45, 2822. (b)
Beak, P.; Kokko, B. J . Tetrahedron Lett. 1983, 24, 561.

Transition Structure Geometries
J . Org. Chem., Vol. 64, No. 14, 1999 5223
Sch em e 3
we do not account to the rates of competing reactions. It
is nonetheless interesting these results show that the
yields of products are higher for the more substituted
carbanions.
Con clu sion s. Endocyclic restriction tests with 5 and
9 show that nucleophilic substitutions at neutral nitrogen
requires a large angle between the nucleophile and the
leaving group. A lack of isotopic scrambling in 12
excludes an oriented ion pair for these nucleophilic
substitutions at neutral nitrogen. Although we were
unable to carry out an endocyclic restriction test in a
large ring for substitution at anionic nitrogen, the
intermolecular reactions in the prospectively small endo-
cyclic rings are consistent with a requirement for a large
angle between the entering and leaving groups in these
reactions also.7 We suggest the transition states for
substitution at neutral and lithiated nitrogen can be
considered to be a trigonal bipyramidal structures result-
ing from nucleophilic attack from backside of the leaving
group as shown in Scheme 3.1,6,20 The competitive ef-
ficiencies in the neutral and anionic series, with increas-
ing substitution at the carbonionic carbon of the nucleo-
philes affording increased yields of products, while
increasing substitution adjacent to nitrogen of the elec-
trophile leads to decreased yields, are consistent with
trends bimolecular nucleophiles observed in substitutions
at carbon.22 The rationalizations of VSEPR and FMO
theory which model the transition structures for classic
SN2 reactions are applicable and supported by more
sophisticated theory.2 For the reactions of the N-lithio-
alkoxy amides, the displacement at anionic nitrogen by
a formal carbanion is considered to involve association
with the lithium ions, a possibility which was recognized
as an early case of the complex induced proximity
effect.1,6,20,21
The trends in yields for reaction at the anionic nitrogen
alkoxides do not show as much difference between the
differently substituted carbanions as for reactions at
neutral nitrogen (vide supra). To obtain a better measure
of the competition between the butyllithiums, we carried
out competitive reactions for 36. A mixture of 1 equiv of
MeLi and 36 was allowed to react with mixtures of excess
of organolithium reagents. The product ratios were used
to calculate the competitive efficiencies of the organo-
lithium reagents toward amination by 36, corrected for
the change in the amount of each nucleophile available
as a function of the extent of reaction.9 We find that
t-BuLi is ca. 9 times more effective in substitution than
n-BuLi and slightly more effective than s-BuLi as a
nucleophile for reactions with 36.
The effect of steric hindrance adjacent to nitrogen on
the yields of products has been investigated for competi-
tion between 36 and 38. When a mixture of 19 equiv of
38 and 1 equiv of 36 was used for the amination of 1
equiv of t-BuLi, s-BuLi, and n-BuLi, the only products
observed were 39, 40, and 41, respectively, along with
recovered 38. In an experiment in which 4 equiv of 38
and 1 equiv of 36 were allowed to compete for the
amination of 1 equiv of n-BuLi, analysis showed the
presence of a small amount of 48 in addition to 41. These
results show the less sterically hindered 36 to be sub-
stantially more effective in amination than 38 for each
of the butyllithium reagents.
Ack n ow led gm en t. We are grateful to the National
Science Foundation for support of this work.
Su p p or tin g In for m a tion Ava ila ble: Details of the syn-
theses and reactions reported. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O990509G
(21) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356.
(22) Correlations of basicity and nucleophilicity have been observed
in SN2 reactions. For example, the nucleophilic constant of triethyl-
amine is greater than that of ammonia. Increasing steric hindrance
in the electrophile is well-known to decrease the rate of SN2 substitu-
tions at carbon.15
These competitive efficiencies for substitution cannot
be taken as rigorous measures of relative reactivity since