Synthesis of enantiomerically enriched isotopically-labelled anilines by (-)-sparteine directed lithiation

Article abstract of DOI:10.1016/j.tetasy.2008.09.014

Anilines bearing benzyl or isopropyl groups isotopically labelled (with ²H or ¹³C) in one of a pair of enantiotopic protons or methyl groups can be made using (-)-sparteine-directed lithiation with an electrophilic quench, followed by deprotection.

Full text of DOI:10.1016/j.tetasy.2008.09.014

Tetrahedron: Asymmetry 19 (2008) 2218–2221
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of enantiomerically enriched isotopically-labelled anilines by
(ꢀ)-sparteine directed lithiation
*
Jonathan Clayden , Loïc Lemiègre , Mark Pickworth
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
a r t i c l e i n f o
a b s t r a c t
Anilines bearing benzyl or isopropyl groups isotopically labelled (with 2H or 13C) in one of a pair of enan-
tiotopic protons or methyl groups can be made using (ꢀ)-sparteine-directed lithiation with an electro-
philic quench, followed by deprotection.
Article history:
Received 1 September 2008
Accepted 17 September 2008
Available online 11 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
H
H H
Ph
D
1. Either
(A) n-BuLi, TMEDA,
tol, —78 ºC, 9 h
O
N
O
N
Ph
As part of an ongoing program of work in which we have used
NMR techniques to study the conformation of putatively helical
oligomers (‘foldamers’)1–6 built from aromatic amides7,8 or
ureas,9,10 we required some enantiomerically enriched aniline
derivatives in which each of a pair of otherwise enantiotopic nuclei
(H or C) is selectively labelled with an NMR active or inactive nu-
cleus (1H vs 2H; 12C vs 13C). Herein we report the methods we used
(Scheme 1).
or (B) n-BuLi,
(—)-sparteine 2, tol,
—78 ºC, 9 h
1
1
d-
OMe
OMe
2. MeOD
1
Conditions A:( )-d- , 99% d
1
Conditions B:(R)-d- , 97% d
CF3CO2H,
CH2Cl2, rt, 12 h
H D
2. Results and discussion
HN
Ph
( )-d-3 96%
N
N
Benzylic amine derivatives may be functionalized enantioselec-
tively by (ꢀ)-sparteine directed enantioselective deprotonation of
their N-Boc-N-aryl derivatives,11,12 or by chiral lithium amide base
promoted deprotonation of N-benzoyl-N-t-butyl derivatives.13
Deuteration of the configurationally stable lithiated intermediates
provides a method for the synthesis of isotopically labelled pro-
tected amines.
(R)-d-3 96%
(—)-sparteine 2
OMe
Scheme 1. Deuteration by lithiation.
Carbamate 1 was made by the reported method;11,12 it was
deprotonated with n-BuLi in the presence of TMEDA and by n-BuLi
in the presence of (ꢀ)-sparteine 2. The resulting organolithiums
were quenched with MeOD to yield racemic and enantiomerically
enriched d-1 with 97–99% deuteration (by MS and by 1H NMR).
Both samples were deprotected (CF3CO2H) to yield anilines d-3 in
96% yield.
but the enantiomeric purity of neither d-1 nor the amine d-3 has
been reported. We chose to establish the er of d-3 by the formation
of a diastereoisomeric derivative. Formation of the MTP amide 5 of
undeuterated
3
by acylation with Mosher’s acid chloride14
Deuteration of 1 via an enantiomerically enriched organolith-
O
O
H H
H H
Ph
ium has previously been reported to form the (R) isomer of d-1,12
Ph
Ph
Cl
4
HN
Ph
N
MeO CF3
MeO
CF3
py, THF, 12 h
quant.
* Corresponding author. Tel.: +44 (0)161 275 4612/4614; fax: +44 (0)161 275
4939.
E-mail address: j.p.clayden@man.ac.uk (J. Clayden).
Present address: Ecole Nationale Supérieure de Chimie de Rennes, UMR CNRS
6226, Av. G. Leclerc 35700 Rennes, France.
3
5
OMe
OMe
Scheme 2. MTP amide of aniline 3.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.09.014

J. Clayden et al. / Tetrahedron: Asymmetry 19 (2008) 2218–2221
2219
(R)-MTPACl 4 (Scheme 2) gave an excellent yield of the amide 5, in
whose 1H NMR spectrum the benzylic protons showed a clear AB
system (J = 14.0 Hz). Repeating the reaction with racemic d-3
(Scheme 3) gave a mixture of (R,R) and (R,S)-d-5, which conse-
nate 11. As determined by integration of the signals in the 1H
NMR spectrum, 12 was formed with a diastereoisomeric ratio of
87:13, and 13 in a diastereoisomeric ratio of 91:9, implying the
corresponding er’s in 9 and 10, respectively. Enantioselective
methylation of 6 has not previously been reported, but evidently
proceeds with enantioselectivity comparable to that reported for
alkylation with 1-iodoundecane (89:11).20 We assigned an (S)-
absolute stereochemistry to 9 and 10 on the basis of this previous
alkylation.
The synthesis of the analogue of 16 (R = Me) of the potentially
enantiomerically enriched, isotopically labelled cumylamine deriv-
ative 16 (R = Me*) was also attempted (Scheme 5) using the stereo-
specific deprotonation and methylation of 14.11,12 However, the
attempted deprotection of the N-Boc cumylamine 15 led to decom-
position by loss of the stable cumyl cation.22–24
quently showed
a pair of singlets in its NMR spectrum
(D
d = 58 ppb). With (R,R)-d-5 derived from enantiomerically en-
riched (R)-d-3, these singlets were present in a ratio of 70:30,
implying that (R)-d-1 is formed with a 70:30 er. This value is lower
than that reported for related reactions of lithiated 1 with other
electrophiles11,12,15 but nonetheless sufficiently high enough to
be useful for our purposes.
O
H D
HN Ph
H D
Ph
N
Ph
4
MeO CF3
py, THF,12 h
93%
O
Me R
Me R
HN Ph
OMe
OMe
O
N
Ph
( )-d-3
(R,R)+(R,S)-d-5
or (R)-d-3
or (R,R)-d-5
Scheme 3. MTP amide of labelled anilines.
CF3CO2H,
CH2Cl2
1. n-BuLi, TMEDA,
OMe
OMe
tol, —78 °C, 9 h
2. MeI
14
15
(R = H)
rt, 12 h
16 (R = Me)
(R = Me)
For another series of compounds, we required an aniline bear-
ing a 13C or 2H isotopic label in one of the two enantiotopic methyl
groups. Given the reported diverse lithiation chemistry16 of 2-
alkylaryl amides,17–19 anilides,20 and ureas,21 we chose 2-isopropyl
anilines 9 and 10 as our target compounds (Scheme 4).
86%
Scheme 5. Attempted synthesis of labelled cumylamine derivative 16.
3. Conclusion
The methods reported here allowed us to obtain gram quanti-
ties of labelled amines d-3, 9 and 10 in enantiomerically enriched
form. Future reports25 will detail conformational insights gained
by incorporation of the labelled amines d-3, 9 and 10 into oligourea
and oligoamide foldamers.
1. s-BuLi, Et2O,
O
O
—25 °C, 2 h
2. (—)-sparteine,
—25 °C, 45 min
NH
NH Me*
Me
3. –78°C,IMe*,7h
6
7 (Me* = CD3) 81%
4. Experimental
(Me* = 13CH3) 77%
8
General experimental details have been reported recently.26
NCO
10M HCl
EtOH, Δ,
72 h
Me*
4.1. (R)-tert-Butyl-a-deuterobenzyl-p-
methoxyphenylcarbamate, (R)-d-1
NH2 Me*
11
H
N
H
N
The method reported by Beak11,12 was employed. To a solution
of (ꢀ)-sparteine (0.46 cm3, 2.0 mmol) in toluene (2.0 cm3) at
ꢀ78 °C was added n-BuLi (1.0 cm3, 2.0 mmol, 2.0 M). The reaction
mixture was stirred for 30 min at ꢀ78 °C and then a solution of
N-Boc-N-(p-methoxyphenyl)benzylamine 1 (0.50 g, 1.6 mmol) in
toluene (1.6 cm3) was added. The resulting reaction mixture was
stirred at ꢀ78 °C for 9 h and methanol-d1 (0.10 cm3, 2.20 mmol)
added. After stirring for 3 h at ꢀ78 °C, the reaction was warmed
to room temperature for 10 h. Water (10 cm3) was added and ex-
tracted with EtOAc (3 ꢁ 10 cm3). The combined organic fractions
were dried over MgSO4, filtered and concentrated under reduced
pressure. The residue was purified by flash column chromatogra-
O
9 (Me* = CD3) 85%
10 (Me* = 13CH3) 68%
12 (Me* = CD3)87:13 d.r.
13 (Me* = 13CH3) 91:9 d.r.
Scheme 4. Synthesis of labelled anilines 9 and 10.
Amide 6 was made by standard methods, and was lithiated with
s-BuLi in the presence of (ꢀ)-sparteine.20 Selectivity in the reac-
tions of lithio-6 results from dynamic thermodynamic resolution
of the intermediate organolithium-(ꢀ)-sparteine complex,16 so
the lithiation was held at ꢀ25 °C to ensure full equilibration before
cooling to ꢀ78 °C.20 Two isotopically labelled methyl iodides were
then added: ICD3 and I13CH3, to give an enantiomerically enriched
sample of both 7 and 8 in 81% and 77% yield, respectively.
The pivanilide directing group was hydrolysed by refluxing in
aqueous hydrochloric acid, to yield the amine 9 in 85% yield and
amine 10 in 68% yield. The enantioselectivity of the methylation
was determined by formation of the ureas 12 and 13 in quantita-
tive yield with enantiomerically pure (R)-2-naphthylethyl isocya-
phy (SiO2; petrol to 5% EtOAc in petrol) to give tert-butyl-a-deute-
robenzyl-p-methoxyphenylcarbamate d-1 (0.49 g, 97%), as a white
solid, mp 93–95 °C (EtOAc); Rf (20% EtOAc in petrol) 0.63; mmax
(film)/cmꢀ1 2842 (OCH3) and 1716 (C@O); dH (300 MHz; CDCl3)
7.16–7.01 (5H, m, CH-c, CH-d and CH-e), 6.86 (2 H, br, CH-b),
6.61 (2 H, d, J = 9.0, CH-a), 4.60 (1 H, s, CH-f) and 3.54 [3 H, s, (Ar-
OCH3)]; dC (75 MHz; CDCl3) 157.6 (C@O), 155.2 (C), 138.7 (C), 135.7
(C), 128.5 (CH), 128.1 (CH), 127.7 (CH), 127.2 (CH), 113.9 (CH), 80.2

2220
J. Clayden et al. / Tetrahedron: Asymmetry 19 (2008) 2218–2221
(C), 55.4 (ArOCH3), 54.1 (CHD) and 28.4 [(CH3) ꢁ 3]; m/z (ES+) 315
(100%, M+H+); (found: M+H+, 315.1825, C19H23D3NO3 requires
M+H, 315.1819).
4.4. N-
a-Deuterobenzyl-3,3,3-trifluoro-2-methoxy-N-(4-
methoxyphenyl)-2-phenylpropanamide d-5
The same compound was made in its racemic form by the fol-
lowing method. To a solution of TMEDA (0.30 cm3, 2.0 mmol) in
toluene (2.0 cm3) at ꢀ78 °C was added n-BuLi (1.0 cm3, 2.0 mmol,
2.0 M). The reaction mixture was stirred for 30 min at ꢀ78 °C
N-(p-Methoxyphenyl)-
a
-deuterobenzylamine
d-3
(0.15 g,
0.69 mmol) and (R)-(ꢀ)- -methoxy-
a
a
-(trifluoromethyl)phenylace-
tyl chloride 4 (0.18 g, 0.69 mmol) were dissolved in THF (5.0 cm3),
pyridine (0.11 cm3, 1.4 mmol) added and stirred for 12 h at room
temperature. Water (10 cm3) was added and extracted with EtOAc
(3 ꢁ 10 cm3). The combined organic fractions were dried over
MgSO4, filtered and concentrated under reduced pressure. The res-
idue was purified by flash column chromatography (SiO2; petrol to
and
a solution of N-Boc-N-(p-methoxyphenyl)benzylamine 1
(0.50 g, 1.6 mmol) in toluene (1.6 cm3) was added. The resulting
reaction mixture was stirred at ꢀ78 °C for 9 h and methanol-d1
(0.10 cm3, 2.2 mmol) added. After stirring for 3 h at ꢀ78 °C, the
reaction was warmed to room temperature for 10 h. Water
(10 cm3) was added and extracted with EtOAc (3 ꢁ 10 cm3). The
combined organic fractions were dried over MgSO4, filtered and
concentrated under reduced pressure. The residue was purified
by flash column chromatography (SiO2; petrol to 5% EtOAc in pet-
20% EtOAc in petrol) to give N-
a
-deuterobenzyl-3,3,3-trifluoro-2-
d-5
¼ ꢀ105:9 (c 0.2, CH2Cl2);
methoxy-N-(4-methoxyphenyl)-2-phenylpropanamide
(0.28 g, 93%), as a pale yellow oil, ½a D23
ꢂ
Rf (20% EtOAc in petrol) 0.51; mmax (film)/cmꢀ1 2982 (OCH3),
2850 (OCH3), 1652 (C@O) and 1265 (C–F); dH (300 MHz; CDCl3)
7.39–7.26 (14H, m, Armaj and min), 7.26–7.18 (6H, m, Armaj and min),
6.94 (2H, d, J = 9.0, Armaj and min), 6.85 (2H, d, J = 9.0, Armaj and min),
6.55–6.30 (4H, br, Armaj and min), 4.95 (1H, s, CH-amaj), 4.89 (1H, s,
rol) to give tert-butyl-a-deuterobenzyl-p-methoxyphenylcarba-
mate d-1 (0.50 g, 99%), as a white solid, mp 93–95 °C (EtOAc).
4.2. (R)-N-(p-Methoxyphenyl)-a-deuterobenzylamine, (R)-d-3
CH-amin), 3.73 [6H, s, (ArOCH3)maj and min] and 3.57 [6H, q, J = 2.0,
and
(OCH3)maj
min]; dC (75 MHz; CDCl3) 166.3 (C@O)maj, 160.0
and
and
tert-Butyl- -deuterobenzyl-p-methoxyphenylcarbamate (R)-d-
a
(C@O)min, 158.6 (C)maj
min, 137.0 (C)maj
min, 135.6 (C)min
,
,
,
1 (0.30 g, 0.96 mmol) was dissolved in CH2Cl2 (5 cm3) and trifluo-
roacetic acid (1 cm3, 13 mmol) added dropwise. The reaction mix-
ture was stirred at room temperature for 12 h and the solvent
evacuated under reduced pressure. The residue was dissolved in
EtOAc (20 cm3), made basic by washing with saturated NaHCO3
and the two phases separated. The organic fraction was dried over
MgSO4, filtered and concentrated. The residue was purified by flash
column chromatography (SiO2; 10% EtOAc in petrol to EtOAc) to
135.0 (C)maj, 133.2 (C)maj, 131.4 (C)min, 129.7 (CH)maj
and min
129.2 (CH)maj
min, 128.6 (CH)maj
min, 128.1 (CH)maj
and
and
and
and min
128.0 (CH)maj
min, 126.8 (CH)maj
min, 124.0 [q, J = 290.0,
and
and
and
and
(CF3)maj
min], 114.4 (CH)maj
min, 113.2 (CH)maj
min, 85.2
and
maj and
[q, J = 24.8, (C–CF3)maj
min], 55.90 (OCH3)A
min, 55.87
maj and
(OCH3)B
min, 55.6 (CHD)min and 55.5 (CHD)maj; m/z (ES+)
431 (40%, M+H+); (found: M+H+, 431.1688, C24H22DNO3F3 requires
M+H, 431.1687).
give N-(p-methoxyphenyl)-a-deuterobenzylamine (R)-d-3 (0.20 g,
96%), as a brown oil, Rf (20% EtOAc in petrol) 0.10; mmax (film)/
cmꢀ1 3413 (NH) and 2834 (OCH3); dH (300 MHz; CDCl3) 7.46–
7.29 (5H, m, CH-c, CH-d and CH-e), 6.84 (2 H, d, J = 9.0, CH-b),
6.67 (2 H, d, J = 9.0, CH-a), 4.32 (1H, s, CH-f) and 3.80 [4H, s, (Ar-
OCH3) and NH]; dC (75 MHz; CDCl3) 152.5 (C), 142.8 (C), 139.9
(C), 128.9 (CH), 127.9 (CH), 127.5 (CH), 115.2 (CH), 114.4 (CH),
56.1 (ArOCH3) and 49.2 (CHD); m/z (ES+) 215 (100%, M+H+);
(found: M+H+, 215.1300, C14H15DNO requires M+H, 215.1295).
4.5. (S)-2-(1-Methyl-2,2,2-trideuterioethyl)pivanilide 7
The method of Beak20 was employed. Under a nitrogen atmo-
sphere, 2-ethylpivanilide 6 (4.0 g 19.5 mmol, 1 equiv) was dis-
solved in dry Et2O (140 mL). s-BuLi in hexane 1.3 M (31.5 mL,
41.0 mmol, 2.1 equiv) was added at –25 °C and the solution stirred
for 2 h at the same temperature. (ꢀ)-Sparteine (13.0 mL,
56.5 mmol, 2.9 equiv) was added and the mixture was kept at
ꢀ25 °C for 45 min, then cooled to ꢀ78 °C for 30 min. Methyl iodide
(1.46 mL, 23.4 mmol, 1.2 equiv) was then added. The reaction mix-
ture was maintained at ꢀ78 °C for 7 h. MeOH (2 mL) was added fol-
lowed by water (5 mL). The organic phase was washed with H3PO4
0.5 M, dried over MgSO4 and concentrated under reduced pressure.
The pure product 7 was obtained after precipitation in Et2O/petrol
4.3. N-Benzyl-3,3,3-trifluoro-2-methoxy-N-(4-methoxyphenyl)-
2-phenylpropanamide, 5
N-Boc-N-(p-methoxyphenyl)benzylamine 3 (0.04 g, 0.2 mmol)
and (R)-(ꢀ)-
a-methoxy-a-(trifluoromethyl)phenylacetyl chloride
(0.05 g, 0.2 mmol) were dissolved in THF (3.0 cm3), pyridine
(0.11 cm3, 1.4 mmol) added and stirred for 12 h at room tempera-
ture. Water (10 cm3) was added and extracted with EtOAc
(3 ꢁ 10 cm3). The combined organic fractions were dried over
MgSO4, filtered and concentrated under reduced pressure. The res-
idue was purified by flash column chromatography (SiO2; petrol to
(3.5 g, 81%). Mp: 121 °C. IR m
max cmꢀ1: 3319, 2959, 1646, 1504, 755.
1H NMR (300 MHz, CDCl3) d (ppm): 1.26 (3H, d, J = 6.6 Hz), 1.35
(9H, s), 2.96 (1H, q, 6.6 Hz), 7.23 (3H, m), 7.32 (1H, br s), 7.77
(1H, dd, J = 1.8, 7.8 Hz). 13C NMR (75 MHz, CDCl3) d (ppm): 22.70,
27.69, 27.90, 39.66, 124.19, 125.34, 125.55, 126.39, 134.36,
139.57, 176.58. MS (CI/NH3): 223 (MH+, 100). HRMS for
C14H19D3NO (MH+): calcd: 223.1884; found: 223.1884. Elem. Anal.
Calcd for C14H18D3NO: C, 75.63; H, 9.52; N, 6.30. Found: C, 75.33;
H, 9.34; N, 6.18.
20% EtOAc in petrol) to give N-a-benzyl-3,3,3-trifluoro-2-meth-
oxy-N-(4-methoxyphenyl)-2-phenylpropanamide 5 (0.08 g, 97%),
as a colourless oil, ½a D24
¼ ꢀ106 (c 0.4, CH2Cl2); Rf (20% EtOAc in
ꢂ
petrol) 0.51; mmax (film)/cmꢀ1 2977 (OCH3), 2842 (OCH3), 1653
(C@O) and 1265 (C–F); dH (500 MHz; CDCl3) 7.26–7.15 (7H, m,
Ar), 7.15–7.05 (3H, m, Ar), 6.95 (1H, d, J = 9.0, Ar), 6.84 (1H, d,
J = 9.0, Ar), 6.55–6.20 (2H, br, Ar), 4.84 (1 H, d, J = 14.0, CH-a or
CH-b), 4.68 (1H, d, J = 14.0, CH-b or CH-a), 3.61 [3H, s, (ArOCH3)]
and 3.44 [3H, q, J = 2.0, (OCH3)]; dC (125 MHz; CDCl3) 166.2
(C@O), 158.4 (C), 136.8 (C), 134.7 (C), 133.0 (C), 129.4 (CH), 128.9
(CH), 128.3 (CH), 127.9 (CH), 127.7 (CH), 126.6 (CH), 123.7 [q,
J = 289.0, (CF3)] 114.9 (CH), 114.1 (CH), 84.9 [q, J = 24.9, (C–CF3)],
55.7 (OCH3)A, 55.6 (CH2) and 55.2 (OCH3)B; m/z (ES+) 430 (60%,
M+H+); (found: M+H+, 430.1635, C24H23NO3F3 requires M+H,
430.1625).
4.6. (S)-2-(1-13C-Methylethyl)pivanilide 8
The method reported by Beak20 was employed. Under nitrogen
atmosphere, 2-ethylpivanilide 6 (2.39 g 11.7 mmol, 1 equiv) was
dissolved in dry Et2O (80 mL). s-BuLi in hexane 1.3 M (18.9 mL,
24.5 mmol, 2.1 equiv) was added at ꢀ25 °C and the solution stirred
for 2 h at the same temperature. (ꢀ)-Sparteine (7.78 mL,
33.8 mmol, 2.9 equiv) was added and kept at ꢀ25 °C for 45 min
and then cooled to ꢀ78 °C for 30 min before 13C-methyl iodide
(2 g, 14.0 mmol, 1.2 equiv) was added. The reaction mixture was
maintained at ꢀ78 °C until complete reaction (7 h). Then MeOH

J. Clayden et al. / Tetrahedron: Asymmetry 19 (2008) 2218–2221
2221
(2 mL) was added at ꢀ78 °C followed by water (5 mL) at rt. The
organic phase was washed with H3PO4 (0.5 M) then dried over
MgSO4 and concentrated under reduced pressure. The pure prod-
uct 8 was obtained after precipitation in Et2O/petrol followed by
flash chromatography on silica gel (95/5: DCM/AcOEt) (1.97 g,
77%). Mp: 122 °C. IR mmax cmꢀ1: 3317, 2959, 1644, 1503, 757,
736. 1H NMR (500 MHz, CDCl3) d (ppm): 1.27 (3H, dd, J = 6.9,
126 Hz), 1.27 (3H, dd, J = 5.3, 6.9 Hz), 1.35 (9H, s), 2.97 (1H, dsept,
J = 2.1, 6.9 Hz), 7.15 (1H, dt, J = 1.5, 7.5 Hz), 7.20 (1H, dt, J = 1.5,
7.5 Hz), 7.27 (1H, dd, J = 1.6, 7.5 Hz), 7.32 (1H, br s), 7.77 (1H, d,
J = 7.8 Hz). 13C NMR (75 MHz, CDCl3) d (ppm): 22.77, 27.68, 27.78
(1C, d, J = 109 Hz), 39.65, 124.24, 125.35, 125.56, 126.38, 134.36,
139.65, 176.58. MS (CI/NH3): 221 (MH+, 100). HRMS for
C1313CH22NO (MH+): calcd: 221.1729; found: 221.1726. Elem. Anal.
Calcd for C1313CH21NO: C, 76.32; H, 9.61; N, 6.36. Found: C, 76.67;
H, 9.84; N, 6.35.
added n-BuLi (1.0 cm3, 2.0 mmol, 2.0 M). The reaction mixture was
stirred for 30 min at –78 °C and then a solution of N-Boc-N-(p-
methoxyphenyl)-a-methylbenzylamine 14 (0.52 g, 1.6 mmol) in
toluene (1.6 cm3) was added. The resulting reaction mixture was
stirred at –78 °C for 9 h and then methyl iodide (0.12 cm3,
2.0 mmol) added. After stirring for 3 h at ꢀ78 °C, the reaction
was stirred at room temperature for 10 h. Water (10 cm3) was
added and extracted with EtOAc (3 ꢁ 10 cm3). The combined or-
ganic fractions were dried over MgSO4, filtered and concentrated
under reduced pressure. The residue was purified by flash column
chromatography (SiO2; petrol to 5% EtOAc in petrol) to give N-Boc-
N-(p-methoxyphenyl)-a,a-dimethylbenzylamine 15 (0.59 g, 86%),
as a colourless oil; Rf (20% EtOAc in petrol) 0.42; mmax (film)/cmꢀ1
2845 (OCH3) and 1699 (C@O); dH (500 MHz; CDCl3) 7.44 (2H, dd,
J = 8.0 and 1.0, CH-c), 7.27 (2H, dd, J = 8.0 and 7.5, CH-d), 7.19
(2H, d, J = 8.5, CH-a), 7.14 (1H, tt, J = 7.5 and 1.0, CH-e), 6.85 (2 H,
d, J = 8.5, CH-b), 3.75 [3 H, s, (ArOCH3)], 1.43 [6H, s, (CH3) ꢁ 2]
and 1.02 [9H, s, (CH3) ꢁ 3]; dC (75 MHz; CDCl3) 158.7 (C@O),
155.9 (C), 150.7 (C), 134.5 (C), 131.3 (CH), 128.3 (CH), 126.0 (CH),
124.7 (CH), 114.2 (CH), 80.2 (C), 61.6 (C), 55.7 (ArOCH3), 30.6
[(CH3) ꢁ 2] and 28.3 [(CH3) ꢁ 3]; m/z (ES+) 342 (100%, M+H+);
(found: M+H+, 342.2075, C21H28NO3 requires M+H, 342.2069).
4.7. (S)-2-(1-Methyl-2,2,2-trideuterioethyl)aniline 9
Pivanilide 7 (3.1 g, 13.9 mmol, 1 equiv) was dissolved in EtOH
(75 mL) and HClaq 10 M (30 mL). The reaction mixture was heated
at reflux for 72 h before NaOH 6 M (50 mL) was added. The aque-
ous phase was extracted with AcOEt and dried over MgSO4.
Acid–base washing provided 1.65 g of pure product 9 (85%). The
er was determined by derivatisation with phenylethylisocyanate
11 to be 87:13. IR mmax cmꢀ1: 3467, 3376, 2959, 1621, 1495, 749.
1H NMR (500 MHz, CDCl3) d (ppm): 1.27 (3H, d, J = 7.0 Hz), 2.89
(1H, q, 7.0 Hz), 3.65 (2H, br s), 6.69 (1H, dd, 1.0, 8.0 Hz), 6.79
(1H, t, J = 7.0 Hz), 7.03 (1H, t, J = 7.5 Hz), 7.15 (1H, d, J = 7.5 Hz).
13C NMR (75 MHz, CDCl3) d (ppm): 22.16, 27.38, 115.76, 118.97,
125.36, 126.48, 132.61, 143.27. MS (CI/NH3): 139 (MH+, 100).
HRMS for C9H11D3N (MH+): calcd: 139.1309; found: 139.1311.
Elem. Anal. Calcd for C9H10D3N: C, 78.20; H, 9.48; N, 10.13. Found:
C, 78.04; H, 9.89; N, 10.10.
Acknowledgments
We are grateful to the Leverhulme Trust, to the EPSRC and to
Pfizer Ltd for support of this project.
References
1. Foldamers; Hecht, S., Huc, I., Eds.; Wiley-VCH: Weinheim, 2007.
2. Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem. Rev. 2001, 101,
3893.
3. Gellman, S. H. Acc. Chem. Res. 1998, 31, 173.
4. Huc, I. Eur. J. Org. Chem. 2004, 17.
5. Nakano, T.; Okamoto, Y. Chem. Rev. 2001, 101, 4013.
6. Cornelissen, J. H. L. M.; Rowan, A. E.; Nolte, R. J. M.; Sommerdijk, N. A. J. M.
Chem. Rev. 2001, 101, 4039.
4.8. (S)-2-(1-13C-Methylethyl)aniline 10
7. Clayden, J.; Lund, A.; Vallverdú, L.; Helliwell, M. Nature (London) 2004, 431, 966.
8. Clayden, J.; Vallverdú, L.; Helliwell, M. Chem. Commun. 2007, 2357.
9. Clayden, J.; Lemiègre, L.; Helliwell, M. J. Org. Chem. 2007, 72, 2302.
10. Clayden, J.; Lemiègre, L.; Morris, G. A.; Pickworth, M.; Snape, T. J.; Jones, L. H.
J. Am. Chem. Soc., in press.
11. Park, Y. S.; Boys, M. L.; Beak, P. J. Am. Chem. Soc. 1996, 118, 3757.
12. Faibish, N. C.; Park, Y. S.; Lee, S.; Beak, P. J. Am. Chem. Soc. 1997, 119, 11561.
13. Clayden, J.; Menet, C. J.; Mansfield, D. J. Chem. Commun. 2002, 38.
14. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543.
15. Assignment of (R) stereochemistry to d-3 is based on previous assumptions
(see Refs. 11 and 12) that deuteration is retentive. We have reported examples
of related N-substituted benzyllithiums which deuterate with variable
stereospecificity (see Clayden, J.; Dufour, J.; Grainger, D.; Helliwell, M. J. Am.
Chem. Soc. 2007, 129, 7488). Previous reports (Refs. 11 and 12) did not quantify
the er of deuterated products.
16. Clayden, J. Organolithiums Selectivity for Synthesis; Pergamon: Oxford, 2002.
17. Court, J. J.; Hlasta, D. J. Tetrahedron Lett. 1996, 37, 1335.
18. Clayden, J.; Pink, J. H.; Westlund, N.; Wilson, F. X. Tetrahedron Lett. 1998, 39,
8377.
19. Clark, R. D.; Jahangir, A. Org. React. 1995, 47, 1.
20. Basu, A.; Beak, P. J. Am. Chem. Soc. 1996, 118, 1575.
21. Clayden, J.; Dufour, J. Tetrahedron Lett. 2006, 47, 6945; Clayden, J.; Turner, H.;
Pickworth, M.; Adler, T. Org. Lett. 2005, 7, 3147; Clayden, J.; Turner, H.;
Helliwell, M.; Moir, E. J. Org. Chem. 2008, 73, 4415.
The pivanilide 8 (1.8 g, 8.18 mmol, 1 equiv) was dissolved in
EtOH (25 mL) and HClaq 10 M (20 mL). The reaction mixture was
refluxed for 72 h before NaOH 6 M (50 mL) was added. The aque-
ous phase was extracted with AcOEt and dried over MgSO4.
Acid–base washing provided 750 mg of pure product 10 (68%).
The er was determined by derivatisation with phenylethylisocya-
nate 11 to be 91:9. IR mmax cmꢀ1: 3386, 2958, 1619, 1497, 748.
1H NMR (500 MHz, CDCl3) d (ppm): 1.27 (3H, dd, J = 6.8, 126 Hz),
1.27 (3H, dd, J = 5.4, 6.8 Hz), 2.92 (1H, dsept, J = 1.9, 6.8 Hz), 3.79
(2H, br s), 6.70 (1H, d, J = 7.9 Hz), 6.80 (1H, t, J = 7.5 Hz), 7.03 (1H,
dt, J = 1.4, 7.5 Hz), 7.16 (1H, dd, J = 1.3, 7.7 Hz). 13C NMR (75 MHz,
CDCl3) d (ppm): 22.27, 27.52 (1C, d, J = 109 Hz), 115.91, 119.15,
125.39, 126.50, 135.07, 143.01. MS (CI/NH3): 137 (MH+, 100).
HRMS for C813CH14N (MH+): calcd: 137.1154; found: 137.1158.
Elem. Anal. Calcd for C813CH13N: C, 79.37; H, 9.62; N, 10.28. Found:
C, 79.30; H, 9.92; N, 10.56.
22. Clayden, J.; Menet, C. J.; Mansfield, D. J. Org. Lett. 2000, 2, 4229.
23. Metallinos, C.; Nerdinger, S.; Snieckus, V. Org. Lett. 1999, 1, 1183.
24. Metallinos, C. Synlett 2002, 1556.
25. For recent developments, see Refs. 9 and 10.
26. Clayden, J.; Hennecke, U. Org. Lett. 2008, in press.
4.9. N-Boc-N-(p-methoxyphenyl)-a,a-dimethylbenzylamine, 15
The method reported by Beak11,12 was employed. To a solution
of TMEDA (0.30 cm3, 2.0 mmol) in toluene (2.0 cm3) at ꢀ78 °C was