Solution phase structures of enantiopure and racemic lithium N-benzyl-N-(α-methylbenzyl)amide in THF: Low temperature 6Li and 15N NMR spectroscopic studies

Article abstract of DOI:10.1016/j.tetasy.2013.07.001

The antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide are highly efficient enantiopure ammonia equivalents for the asymmetric synthesis of β-amino acid derivatives via conjugate addition to α,β- unsaturated esters. ⁶Li and ¹⁵N NM

Full text of DOI:10.1016/j.tetasy.2013.07.001

Tetrahedron: Asymmetry 24 (2013) 947–952
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Solution phase structures of enantiopure and racemic lithium
6
N-benzyl-N-(
a
-methylbenzyl)amide in THF: low temperature Li and
15N NMR spectroscopic studies
⇑
Timothy D. W. Claridge, Stephen G. Davies , Dennis Kruchinin, Barbara Odell, Paul M. Roberts,
Angela J. Russell, James E. Thomson, Steven M. Toms
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 June 2013
Accepted 1 July 2013
The antipodes of lithium N-benzyl-N-(
equivalents for the asymmetric synthesis of b-amino acid derivatives via conjugate addition to
a
-methylbenzyl)amide are highly efficient enantiopure ammonia
,b-unsat-
urated esters. 6Li and 15N NMR spectroscopic studies of doubly labelled 6lithium (S)-15N-benzyl-15N-(
a
a-
methylbenzyl)amide in THF at low temperature reveal the presence of lithium amide dimers as the only
observable species. Either a monomeric or dimeric lithium amide reactive species can be accommodated
within the transition state mnemonic for this class of conjugate addition reaction. This enantiopure lith-
ium amide offers unique opportunities over achiral (e.g., lithium dibenzylamide) and C2-symmetric (e.g.,
lithium bis-N,N-
a-methylbenzylamide) counterparts for further mechanistic study owing to the ready
distinction of the various dimers formed.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
being accommodated within these calculations.12 Henderson et al.13
and Andrews et al.14 have independently shown that enantiopure
Achiral lithium amides such as lithium diisopropylamide
(LDA),1 lithium hexamethyldisilylazide (LiHMDS) and lithium
2,2,6,6-tetramethylpiperidide (LiTMP)2 are ubiquitous throughout
organic chemistry as strong, non-nucleophilic bases. Chiral lithium
amides, meanwhile, have been employed to promote a range of
enantioselective reactions3 including nucleophilic additions to pro-
chiral carbonyl compounds,4 aldol reactions,5 rearrangements,6
and desymmetrisations.7 As a result of these applications, a consid-
erable amount of research has been directed towards understand-
ing the structures (and thence reactivities) of both achiral and
chiral lithium amides both in solution and the solid state, with sol-
vent, exchange of lithium for another alkali metal, lithium solvat-
ing additives and the presence of salts all having been shown to
play a defining role in the structure and reactivity of lithium
amides.8 For example, LDA in THF has been shown to exist as a
disolvated dimer over a range of concentrations.9
lithium N-benzyl-N-(a-methylbenzyl)amide/THF complexes are di-
meric in the solid state, whilst Koga et al. showed (by 6Li and 15N
NMR spectroscopic analysis) that the related enantiopure (C2-sym-
metric) lithium bis-N,N-a-methylbenzylamide is dimeric in solution
in THF at low temperature.15 In an effort to further facilitate under-
standing of the origin of asymmetric induction in our lithium amide
conjugate addition reaction, we have examined the solution struc-
ture of both enantiopure and racemic lithium N-benzyl-N-(a-meth-
ylbenzyl)amide via 6Li and 15N NMR spectroscopic analyses of
doubly labelled material,16,17 and report the results of these studies
herein.
2. Results and discussion
Initial studies were directed towards the development of an
efficient asymmetric synthesis of enantiopure (S)-15N-benzyl-15N-
(a
-methylbenzyl)amine (S)-15N-7. Following an established proce-
We have pioneered the use of the antipodes of lithium N-benzyl-
dure,18 acylation of -valine derived SuperQuat 119 with BnCOCl
L
N-(a-methylbenzyl)amide as enantiopure ammonia equivalents for
diastereoselective conjugate additions to
a,b-unsaturated esters
gave 2 in 97% yield. Treatment of 2 with LiHMDS followed by
MeI gave 3 in 97:3 dr, which was isolated in 84% yield and >99:1
dr.18 Hydrolysis of 3 was achieved using LiOH, which provided acid
(S)-4 in 98% yield and >98% ee. Addition of 15NH4Cl (98 atom % 15N)
to a solution of the acyl chloride derived from (S)-4 under
Schotten–Baumann conditions20 gave amide (S)-15N-5 in 98% yield
from (S)-4 (or 94% yield from 15NH4Cl).21 Hoffman-type rearrange-
ment of (S)-15N-5 upon treatment with PhI(OCOCF3)2 [prepared
and amides.10,11 Based upon molecular modelling calculations, we
have proposed a transition state mnemonic to rationalise and reli-
ably predict the stereochemical outcome for this class of reaction,
with either a monomeric or dimeric lithium amide reactive species
⇑
Corresponding author.
E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.07.001

948
T. D. W. Claridge et al. / Tetrahedron: Asymmetry 24 (2013) 947–952
Ph
Ph
Ph
Ph
9 : 10 Ph
Ph
Ph
Li
Li
Li
Li
(i)
(ii)
Ph
15N
6Li
N
N
N
N
5.5 : 1.0
HN
O
N
O
N
O
Ph
Ph
97:3 dr
Ph
Ph
(S)-6Li-15N-8
trans-(S,S)-9
solution in -THF
d8
cis-(S,S)-10
O
O
O
O
O
1
2, 97%
3, 84%, >99:1 dr
(iii)
(A) 6Li NMR spectrum of (S)-6Li-15N-8.
Ph
(vi)
(v)
(iv)
15NH2
OH
Ph
15N
H
Ph
15NH2
Ph
Ph
O
O
(S)-15N-7, 98%
(S)-15N- 6, 96%
(S)-15N-5, 98%
(S)-4, 98%
>98% ee
>98% ee
>98% ee
>98% ee
Scheme 1. Reagents and conditions: (i) BuLi, THF, ꢀ78 °C, 30 min, then BnCOCl,
ꢀ78 °C to rt, 1 h; (ii) LiHMDS, THF, ꢀ78 °C, 30 min, then MeI, ꢀ78 °C to rt, 12 h; (iii)
LiOH (2.0 M, aq), THF, rt, 12 h; (iv) SOCl2, benzotriazole, CH2Cl2, 0 °C, 20 min, then
15NH4Cl, Et2O, NaOH (10 M, aq), 0 °C, 30 min; (v) PhI(OCOCF3)2, MeCN, H2O, rt, 8 h;
(vi) PhCHO, EtOH, reflux, 4 h, then NaBH4, 0 °C to rt, 3 days.
from PhI(OAc)2 and F3CCO2H]22 gave (S)-15N-6 in 96% yield.
Condensation of (S)-15N-6 with PhCHO in EtOH followed by treat-
ment with NaBH4 gave (S)-15N-7 in 98% yield, >98% ee,23 and with
>98% 15N incorporation as determined by mass spectrometry
(Scheme 1). The racemate (RS)-15N-7 was similarly prepared, in
93% overall yield and with >98% 15N incorporation, starting from
commercially available acid (RS)-4.
Bu6Li was synthesised via sonication of BuCl and 6Li chunks in
hexane for 16 h; the resultant purple solution was then allowed
to stand for two days at rt to allow precipitation of 6LiCl. The clear
solution was then decanted and filtered through flame-dried
CeliteÒ under an argon atmosphere.24 Titration of the filtrate
against diphenylacetic acid established the concentration of this
solution of Bu6Li as 0.6 M, indicating a 54% yield. Enantiopure lith-
ium amide (S)-6Li-15N-8 was prepared in situ, upon treatment of a
solution of (S)-15N-7 in THF-d8 in an NMR tube25 with Bu6Li, under
an argon atmosphere using standard vacuum line techniques
(Scheme 2). A similar procedure applied to (RS)-15N-7 gave a solu-
tion of racemic lithium amide (RS)-6Li-15N-8 in THF-d8.
15N NMR spectrum of (S)-6Li-15N-8.
(B)
The analysis of (S)-6Li-15N-8 by 6Li NMR spectroscopy17 at 173 K
(ꢀ100 °C), showed the presence of three triplet peaks centred on
dLi 1.38, 1.90 and 2.42 ppm (with associated coupling constants
of 5.0, 5.0 and 4.4 Hz) in a respective 2.7:1.0:2.7 ratio, indicating
the presence of three distinct environments for 6Li nuclei. The trip-
let splitting pattern is consistent with each 6Li nucleus directly
coupling to two equivalent 15N nuclei (for which I = ½), which sug-
gests the presence of lithium amide dimers; no evidence for the
existence of any other species was apparent. For enantiopure (S)-
8, there exist two possible C2-symmetric dimers, trans-(S,S)-9 and
cis-(S,S)-10. The former, trans-(S,S)-9, has the two Li nuclei in
chemically and magnetically inequivalent environments, whilst
the latter, cis-(S,S)-10, has both Li nuclei in chemically and magnet-
ically equivalent environments. These data therefore suggest that
the major species present in solution is dimer trans-(S,S)-9, and
that the ratio of trans-(S,S)-9 to cis-(S,S)-10 is ꢁ5.5:1. Both of the
N nuclei in 9 and both of the N nuclei in 10 are in equivalent envi-
ronments and thus, as expected, the 15N NMR spectrum17 of
Figure 1. 6Li and 15N NMR spectra of (S)-6Li-15N-8 at 173 K.
(S)-6Li-15N-8 at 173 K comprised only two peaks of approximate
quintet splitting (4.4 < JNLi < 5.0 Hz), centred on dN 65.1 and 69.5 ppm,
in a 5.5:1.0 ratio respectively. The relative intensities within the
approximate quintets of 1:2:3:2:1 are consistent with each 15N nu-
cleus coupling to two 6Li nuclei (for which I = 1), providing further
support for the presence of dimers 9 and 10 (Fig. 1).
A
6Li–6Li EXSY indicated exchange between the ‘inner’ triplet
(centred on dLi 1.90 ppm, corresponding to 10) and both of the ‘out-
er’ triplets (centred on dLi 1.38 and 2.42 ppm, corresponding to 9),
although no exchange between the two triplet peaks associated
with 9 was observed. This is indicative of equilibration of 9 and
10 occurring via a non-dissociative mechanism (i.e., ring-opening
via a LiꢀN bond breaking process followed by rotation and
ring-closure).26 Direct exchange between the two triplet peaks
associated with 9 would be observed if it were to fully dissociate
and then reform, suggesting that this process is slow relative to
the NMR timescale. Addition of 0.5 equiv of tert-butyl cinnamate
Ph
(i)
(ii)
15N
6Li
Cl
6Li
Ph
BuCl
Bu6Li
54%, 0.6 M in hexane
(S)-6Li-15N-8
solution in THF-
d8
Scheme 2. Reagents and conditions: (i) 6Li chunks, hexane, rt, ꢂ))), 16 h, then rt,
2 days; (ii) (S)-15N-7, THF-d8, 0 °C then ꢀ78 °C.

T. D. W. Claridge et al. / Tetrahedron: Asymmetry 24 (2013) 947–952
949
(in 0.1 equiv portions) to the solution of (S)-6Li-15N-827 produced
no significant difference in the 5.5:1.0 ratio of 9 to 10, again consis-
tent with this being the equilibrium ratio but hence precluding any
potential insight into the relative consumption of 9 versus 10 dur-
ing the course of the conjugate addition reaction. Interestingly,
however, two new doublet signals appeared in the 6Li NMR spec-
trum (at dLi 0.35 and 1.36 ppm) as tert-butyl cinnamate was added;
in the presence of 0.5 equiv of tert-butyl cinnamate these were the
only detectable signals, suggesting that a 1:1 lithium b-amino (Z)-
enolate/lithium amide complex (in which each 6Li nucleus is con-
nected to only one 15N nucleus) had formed in preference to either
of dimers 9 or 10 (Fig. 2).
dimers 11 and 12 (in a 2:1 ratio, respectively). A 6Li–6Li EXSY
experiment indicated exchange between both of the ‘outer’ triplets
and the ‘inner’ triplet, supporting the presence of 11 (with the Li
nuclei in non-equivalent environments) which undergoes ex-
change via a non-dissociative mechanism with 12 (with the Li nu-
clei in equivalent environments). Direct exchange between the two
triplet peaks associated with 11 was not observed and neither was
there any evidence for exchange of 9 or 10 with 11 or 12, again
consistent with full dissociation and reformation of the various di-
mers being slow relative to the NMR timescale. The 15N NMR spec-
trum17 of (RS)-6Li-15N-8 at 173 K revealed the presence of four,
1:2:3:2:1-quintet signals in the ratios 6.3:5.2:2.6:1.0. As before,
two of these signals correspond to dimers trans-(RS,RS)-9 and cis-
(RS,RS)-10, in the ratio 6.3:1.0, whilst the 2:1 ratio of the other
two signals compares favourably with the ratio of cis-(RS,SR)-11
to trans-(RS,SR)-12 obtained from the 6Li NMR spectrum. From
these data, it can be concluded that (RS)-6Li-15N-8 exists as a mix-
ture of all possible diastereoisomeric dimers 9, 10, 11 and 12 in the
ratio 6.3:1.0:5.2:2.6, respectively. The ratio of 9 to 10 is 6.3:1.0 [in
contrast to 5.5:1.0 observed for (S)-6Li-15N-8] and the ratio of 11 to
12 is 2.0:1.0, whilst the ratio of (9 + 10) to (11 + 12) is 1.0:1.132
(Fig. 3).
Variable temperature 6Li and 15N NMR spectra (recorded be-
tween 173 K and 273 K, in 10 K intervals) revealed similar behav-
iour: peak broadening was initially noted, with eventual
coalescence at approximately 223 K, consistent with much more
rapid exchange at higher temperatures. A single peak was observed
at 273 K and is attributed to the time averaged populations of 6Li
and 15N nuclei in various oligomers at this temperature. It is note-
worthy that the 5.5:1.0 ratio of 9 to 10 decreased before coales-
cence, indicating an increase in the population of 10 at higher
temperatures: for example, at 193 K the ratio of 9 to 10 was
3.6:1.0. From these VT 6Li NMR spectra it is possible to evaluate
the approximate value of the free energy for the process that ef-
fects the coalescence of the two triplet peaks attributed to dimer
9.28 The Eyring equation may be written as:
Variable temperature 6Li and 15N NMR spectroscopic analysis of
(RS)-6Li-15N-8 showed similar behaviour to that observed for
(S)-6Li-15N-8, with initial line broadening and eventual coalescence
being observed as the temperature of the sample was increased,
consistent with an increased rate of exchange between dimers
9–12. Empirical analysis also indicated a change in the dimer ratio
at higher temperatures, consistent with a shift in the position of
equilibrium. The simultaneous increase in the rate of exchange
and shift in the position of equilibrium precluded calculation of
the rates of exchange (and hence free energy of activation) from
line-broadening analysis in this case.
D
Gz ¼ RT½lnðkBT=kchÞꢃ;
where T is the temperature of coalescence (in K), kc is the rate of
coalescence (in Hz), and the other symbols have their usual mean-
ings.29 An approximate value of kc may be determined directly from
the NMR spectrum as:
p
kc ¼
D
dvð
p=
2Þ;
3. Conclusion
where
D
dv is the difference in the chemical shifts of the two peaks
in question (in Hz).30 Taking the coalescence temperature as 223 K
and the difference in the chemical shifts of the two triplet signals
In conclusion, an efficient procedure for the synthesis of
(S)-15N-benzyl-15N-(
a-methylbenzyl)amine has been devised,
associated with 9 as 76.5 Hz, then
D
Gà ꢄ +45 kJ molꢀ1 31
.
Analysis of (RS)-6Li-15N-8 by 6Li NMR spectroscopy17 at 173 K
gave a more complex spectrum compared to that obtained from
enantiopure (S)-6Li-15N-8. Not unexpectedly, signals associated
with dimers trans-(RS,RS)-9 and cis-(RS,RS)-10, comprising two
lithium amide monomers with the same configuration, were pres-
ent. However, for (RS)-6Li-15N-8 there also exists the possibility of
formation of dimers cis-(RS,SR)-11 and trans-(RS,SR)-12, compris-
ing two lithium amide monomers with opposite configurations.
Subtraction of the 6Li NMR spectrum of (S)-6Li-15N-8 from that of
(RS)-6Li-15N-8 gave a spectrum containing three triplet peaks cen-
tred on dLi 1.37, 1.97 and 2.62 ppm in a respective 1:1:1 ratio; it
was postulated that these signals arose due to the presence of
starting from (S)-2-phenylpropanoic acid and using a Hoffman-
type rearrangement as the key step. Deprotonation of a solution
of this amine in THF-d8 with Bu6Li at low temperature gave a solu-
tion of the corresponding doubly labelled 6Li/15N lithium amide,
which is known to be a versatile enantiopure ammonia equivalent
in conjugate addition reactions to a range of
a,b-unsaturated
esters. Analysis of this species by 6Li and 15N NMR spectroscopy re-
veals the presence of lithium amide dimers as the only observable
species. Although a lithium amide dimer may not necessarily rep-
resent the reactive species for conjugate addition reaction, either a
monomeric or dimeric reactive species is accommodated by our
transition state mnemonic for this class of reaction. As rapid lith-
ium exchange within the dimers (via a ring-opening and ring-clos-
ing process) was observed, this suggests that the active species for
conjugate addition is most likely either a ring-open or ring-closed
dimeric lithium amide. The ready distinction of the various dimers
of this lithium amide, as compared to achiral (e.g., lithium dib-
CO2tBu
6Li
6Li
Ph
15
R215N
*
O
Ph
*
NR2
Ph
15N
6Li
(0.5 equiv)
enzylamide) and C2-symmetric (e.g., lithium bis-N,N-a-methylben-
zylamide) counterparts, presents unique opportunities for further
mechanistic study.
Ph
OtBu
(S)-6Li-15N-8
putative 1:1 lithium β-amino (Z)-enolate/lithium
amide complex [15NR2 = (S)-15N-benzyl-
*
solution in d8-THF
15N-(α-methylbenzyl)amino]
4. Experimental section
Ph
Ph
Ph
Ph
9 : 10 Ph
5.5 : 1.0
Ph
Ph
Li
Li
Li
Li
N
N
N
N
4.1. General experimental details
Ph
Reactions involving moisture-sensitive reagents were carried
out under a nitrogen atmosphere using standard vacuum line
techniques and glassware that was flame dried and cooled under
trans-(S,S)-9
-(
,
)-10
cis S S
Figure 2. Addition of tert-butyl cinnamate to a solution of (S)-6Li-15N-8.

950
T. D. W. Claridge et al. / Tetrahedron: Asymmetry 24 (2013) 947–952
Ph
Melting points are uncorrected. Specific rotations are reported
in 10ꢀ1 deg cm2 gꢀ1 and concentrations in g/100 mL. 1H NMR spec-
tra were recorded at ambient temperature in CDCl3. 6Li and 15N
NMR spectra were recorded on a Bruker AV2500 instrument
equipped with a BBO probe, at 173 K in THF-d8. 6Li spectra were
referenced to 1.0 M aq LiCl and 15N spectra were referenced to li-
quid NH3 at 298 K. 6Li–6Li EXSY spectra were recorded using the
standard phase sensitive NOESY pulse sequence, 64 scans, with
D1 = 0.5 s and D8 = 400 ms.
Ph
Ph
Ph
Ph
9 : 10 Ph
Ph
Ph
Li
Li
Li
Li
Ph
15N
6Li
N
N
N
N
6.3 : 1.0
Ph
(RS)-6Li/15N-8
solution in d8-THF
trans-(RS ,RS)-9
cis-(RS,RS)-10
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
11 : 12
Li
Li
Li
Li
N
N
N
N
2.0 : 1.0
4.2. (S)-N(3)-Phenylacetyl-4-isopropyl-5,5-dimethyloxazolidin-
2-one 2
cis-(RS,SR)-11
trans-(RS ,SR)-12
(A) 6Li NMR spectrum of (RS)-6Li-15N-8.
BuLi (2.5 M in hexanes, 0.84 mL, 2.10 mmol) was added drop-
wise to a stirred solution of 119 (300 mg, 1.91 mmol) in THF
(20 mL) at ꢀ78 °C. After 30 min, phenylacetyl chloride (383 mg,
2.48 mmol) was added and stirring was continued for a further
30 min at ꢀ78 °C. The reaction mixture was then allowed to warm
to rt over 30 min before being quenched with satd aq NH4Cl (5 mL).
The resultant mixture was extracted with EtOAc (3 ꢅ 20 mL) and
the combined organic extracts were washed sequentially with satd
aq NaHCO3 (50 mL) and brine (50 mL), then dried and concentrated
in vacuo. Purification via flash column chromatography (eluent
pentane/EtOAc, 15:1) gave 2 as a colourless oil (512 mg, 97%);18
½
a 2D5
ꢃ
þ 52:2 (c 1.0 in CHCl3); dH (400 MHz, CDCl3) 0.88 (3H, d, J
6.9, MeCHMe), 0.96 (3H, d, J 6.9, MeCHMe), 1.32 (3H, s, C(5)MeA),
1.50 (3H, s, C(5)MeB), 2.11 (1H, septet d, J 6.9, 3.2, CHMe2), 4.14
(1H, d, J 3.2, C(4)H), 4.26 (1H, d, J 15.0, CHAHBPh), 4.38 (1H, d, J
15.0, CHAHBPh), 7.25–7.36 (5H, m, Ph).
4.3. (S,S)-N(3)-20-Phenylpropanoyl-4-isopropyl-5,5-
dimethyloxazolidin-2-one 3
LiHMDS (1.0 M in hexanes, 0.87 mL, 0.87 mmol) was added
dropwise to a stirred solution of 2 (200 mg, 0.73 mmol) in THF
(10 mL) at ꢀ78 °C. After 30 min, MeI (114 mg, 0.80 mmol) was
added and the reaction mixture was allowed to warm to rt over
12 h. The reaction mixture was then quenched with satd aq NH4Cl
(5 mL) and the organic layer was extracted with EtOAc (2 ꢅ 10 mL).
The combined organic extracts were then dried and concentrated
in vacuo to give 3 in 97:3 dr. Purification via flash column chroma-
tography (eluent pentane/EtOAc, 15:1) and recrystallisation
(EtOAc/pentane) gave 3 as a white crystalline solid (176 mg, 84%,
(B) 15N NMR spectrum of (RS)-6Li-15N-8.
>99:1 dr);18 mp 107–108 °C; ½a 2D3
þ 103 (c 1.0 in CHCl3); dH
ꢃ
(400 MHz, CDCl3) 0.99 (3H, d, J 6.8, MeCHMe), 0.99 (3H, s,
C(5)MeA), 1.08 (3H, d, J 6.8, MeCHMe), 1.44 (3H, s, C(5)MeB), 1.53
(3H, d, J 7.0, C(30)H3), 2.15 (1H, septet d, J 6.8, 3.3, CHMe2), 4.02
(1H, d, J 3.3, C(4)H), 5.15 (1H, q, J 7.0, C(20)H), 7.21–7.35 (5H, m, Ph).
4.4. (S)-2-Phenylpropanoic acid 4
2.0 M aq LiOH (10 mL) was added to a stirred solution of 3
(4.20 g, 14.5 mmol) in THF (10 mL) at rt. After 12 h the reaction
mixture was acidified to pH 1 using 2.0 M aq HCl. The aqueous
layer was extracted with Et2O (2 ꢅ 20 mL) and the combined or-
ganic extracts were concentrated in vacuo to give 4 as a colourless
oil (2.13 g, 98%); ½a D23
þ 72:4 (c 1.0 in CHCl3); dH (400 MHz, CDCl3)
ꢃ
1.51 (3H, d, J 5.4, C(3)H3), 3.72 (1H, q, J 5.4, C(2)H), 7.23–7.37 (5H,
m, Ph).
Figure 3. 6Li and 15N NMR spectra of (RS)-6Li-15N-8 at 173 K.
4.5. (S)-15N-2-Phenylpropanamide 5
nitrogen before use. Solvents were dried according to the proce-
dure outlined by Grubbs and co-workers.33 Organic layers were
dried over MgSO4. Thin layer chromatography was performed on
aluminium plates coated with 60 F254 silica. Flash column chroma-
tography was performed on Kieselgel 60 silica.
(S)-4 (2.63 mL, 17.5 mmol) was added to a solution of SOCl2
(1.46 mL, 20.0 mmol) and benzotriazole (2.38 g, 20.0 mmol) in
CH2Cl2 (60 mL) at 0 °C. After 20 min the turbid solution was filtered
through a pad of MgSO4 and concentrated in vacuo. The residue

T. D. W. Claridge et al. / Tetrahedron: Asymmetry 24 (2013) 947–952
951
was dissolved in Et2O (10 mL) the resultant solution was cooled to
0 °C and ice-cold 10 M aq NaOH (10 mL) was added, followed by
15NH4Cl (1.0 g, 18.4 mmol). After 30 min the aqueous layer was ex-
tracted with Et2O (10 mL). The combined organic extracts were
dried and concentrated in vacuo to give (S)-15N-5 as a white crys-
adaptor section and a key operated tubing adapter near the top
quickfit neck) containing a Whatman No. 1 sinter was half-filled
with flame dried Celite and sealed via the top quickfit adaptor with
a suba-seal. The flask was placed under positive pressure of Ar via
the key operated tubing adaptor. A 100 mL, two-necked round-bot-
tomed flask was attached to the Schlenk flask via the lower quickfit
adaptor, and small bore cannula was connected between the sec-
ond neck of the flask and a 250 mL, two-necked round bottomed
flask, which was placed under vacuum.
talline solid (2.64 g, 98%); mp 85–87 °C; ½a D23
þ 62:1 (c 1.0 in
ꢃ
CHCl3); dH (400 MHz, CDCl3) 1.50 (3H, d, J 7.2, C(3)H3), 3.60 (1H,
q, J 7.2, C(2)H), 5.30–5.52 (2H, br s, NH2); 7.28–7.42 (5H, m, Ph).
An analogous procedure starting from (RS)-4 (2.63 mL,
17.5 mmol) gave (RS)-15N-5 as a white crystalline solid (2.71 g,
99%).
The purple Bu6Li solution was transferred via wide bore cannula
onto the bed of flame-dried Celite and filtered under suction into
the first round bottomed flask, then transferred into the second
round bottomed flask (placed in a dry ice-bath at ꢀ78 °C) via can-
nula to give a pale yellow solution of Bu6Li (0.6 M, 53 mL, 54%); dLi
(73.6 MHz, THF-d8, 173 K) 1.57, ꢀ1.09, ꢀ0.37, 0.03, 0.36.
4.6. (S)-15N-
a-Methylbenzylamine 6
I,I-Bis(trifluoroacetoxy)iodobenzene (5.20 g, 12.8 mmol) and
H2O (15 mL) were added sequentially to a stirred solution of
(S)-15N-5 (1.8 g, 12.8 mmol) in MeCN (15 mL) at rt. After 8 h the
reaction mixture was acidified with 10 M aq HCl (3 mL) and
washed with Et2O (2 ꢅ 5 mL).34 The resultant aqueous solution
was then neutralised (to pH 7–8) using 1.0 M aq NaOH and washed
with Et2O (5 ꢅ 10 mL).35 The resultant aqueous solution was then
basified (to pH 14) using 2.0 M aq NaOH and extracted with CH2Cl2
(5 ꢅ 10 mL). The combined organic extracts were dried and con-
centrated in vacuo to give (S)-15N-6 as a colourless oil (1.50 g,
4.9. 6Lithium (S)-15N-benzyl-15N-(
a-methylbenzyl)amide 8
Bu6Li (0.6 M in hexane, 0.45 mL, 0.27 mmoL) was added to a
flame dried NMR tube,25 sealed in a Schlenck tube under Ar, and
carefully placed under vacuum (to avoid bumping). After a period
of 30 min, a solution of (S)-15N-7 (58 mg, 0.27 mmol) in THF-d8
(0.5 mL) was added, and the NMR tube was sealed with a cap
and Nescofilm, and placed in a dry-ice bath at ꢀ78 °C. The resultant
pink, 0.54 M solution of (S)-6Li-15N-8 was analysed by NMR spec-
troscopy;25dLi (73.6 MHz, THF-d8, 173 K) 1.38 (t, J 4.4), 1.90 (t, J
5.0), 2.42 (t, J 5.0); dN (50.7 MHz, THF-d8, 173 K) 65.1 (app qunitet),
69.5 (app quintet).
96%); ½a 2D4
ꢃ
ꢀ 28:4 (c 1.0 in CHCl3); dH (400 MHz, CDCl3) 1.49 (3H,
dd, J 6.6, 3.1, C(
a
)Me), 1.39 (2H, s, NH2), 4.12 (1H, q, J 6.6, C( )H),
a
7.18–7.46 (5H, m, Ph).
An analogous procedure starting from (RS)-15N-5 (1.8 g,
12.8 mmol) gave (RS)-15N-6 as a colourless oil (1.50 g, 96%).
An analogous procedure starting from (RS)-15N-7 (58 mg,
0.27 mmol) gave
a
0.54 M solution of (RS)-6Li-15N-8;25 dLi
4.7. (S)-15N-Benzyl-15N-(
a-methylbenzyl)amine 7
(73.6 MHz, THF-d8, 173 K) 1.37 (app t), 1.90 (t, J 5.0), 1.97 (t, J
4.9), 2.42 (t, J 5.0), 2.62 (t, J 5.1); dN (50.7 MHz, THF-d8, 173 K)
65.2 (app qunitet), 67.8 (app qunitet), 69.5 (app quintet), 71.0
(app quintet).
Benzaldehyde (0.42 mL, 4.2 mmol) was added to a stirred solu-
tion of (S)-5 (500 mg, 4.2 mmol) in EtOH (5 mL) and the resultant
solution was heated at reflux for 4 h. The reaction mixture was
then allowed to cool to rt, and then cooled further to 0 °C. NaBH4
(82 mg, 4.2 mmol) was added portionwise. The resultant white
suspension was allowed to warm to rt and stirred for 3 days. The
mixture was then concentrated in vacuo, the residue was parti-
tioned between CH2Cl2 (10 mL) and H2O (10 mL), and the aqueous
layer was extracted with CH2Cl2 (2 ꢅ 10 mL). The combined organ-
ic extracts were then dried and concentrated in vacuo. The residue
was dissolved in Et2O (2 mL) and the resultant solution was added
dropwise to saturated ethereal HCl (50 mL). The resultant white
suspension was then filtered and the solid was washed with Et2O
(2 ꢅ 5 mL). The resultant white solid was recrystallised (CH2Cl2/
30–40 °C petrol, 1:1), then added portionwise to a stirred solution
of 2.0 M aq NaOH (20 mL) at 0 °C. After 5 min, the mixture was ex-
tracted with CH2Cl2 (3 ꢅ 10 mL). The combined organic extracts
were dried and concentrated in vacuo to give (RS)-15N-7 as a col-
Acknowledgment
The authors would like to thank Dr. P. Aguirre-Etcheverry for
helpful advice.
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dH (400 MHz, CDCl3) 1.45–1.51 (3H, app br s, C(
d, J 13.2, NCHAHBPh), 3.72 (1H, d, J 13.2, NCHAHBPh), 3.80 (1H, q,
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4.8. Butyl6lithium
Finely cut 6Li chunks (1.05 g, 150 mmol) were added to a solu-
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pieces were consumed). The resultant purple solution was then al-
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Meanwhile, a large 5 cm diameter Schlenk-type flask (quickfit
adaptors at both ends with Youngs tap separating the bottom

952
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29. R, ideal gas constant (8.314 J Kꢀ1 molꢀ1); kB, Boltzmann constant
(1.38 ꢅ 1023 J Kꢀ1); h, Planck constant (6.626 ꢅ 10ꢀ34 J s).
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significant difference in the populations of the various dimers present; new
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34. Concentration of these combined Et2O washes gave iodobenzene.
35. Concentration of these combined Et2O washes gave unreacted (S)-15N-5
(58 mg, 3%).