Variations in site of lithiation of N-[2-(4-methoxyphenyl)ethyl]pivalamide - Use in ring substitution

Article abstract of DOI:10.1055/s-0032-1317859

Lithiation of N-[2-(4-methoxyphenyl)ethyl]pivalamide at -20 to 0 °C with three equivalents of n-BuLi in anhydrous THF, followed by reactions with various electrophiles, gives high yields of products involving ring substitution ortho to the pivaloylaminoet

Full text of DOI:10.1055/s-0032-1317859

LETTER
▌117
lVettaerriations in Site of Lithiation of N-[2-(4-Methoxyphenyl)ethyl]pivalamide –
Use in Ring Substitution
Lithiation of N-[2-(4-Methoxyphenyl)ethyl]pivalamide
Keith Smith,* Gamal A. El-Hiti,*1 Mohammed B. Alshammari
School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, UK
Fax +44(29)20870600; E-mail: smithk13@cardiff.ac.uk; E-mail: el-hitiga@cardiff.ac.uk
Received: 07.11.2012; Accepted after revision: 19.11.2012
for example, that treatment of N-(2-methoxybenzyl)piva-
Abstract: Lithiation of N-[2-(4-methoxyphenyl)ethyl]pivalamide
lamide with t-BuLi in THF at –78 °C, followed by reac-
at –20 to 0 °C with three equivalents of n-BuLi in anhydrous THF,
tion with an electrophile, gave substitution ortho to the
followed by reactions with various electrophiles, gives high yields
of products involving ring substitution ortho to the pivaloylamino-
methoxy group selectively,8 in sharp contrast with results
ethyl group, which was unexpected in view of earlier results report- reported by Simig and Schlosser, who showed that lithia-
ed with t-BuLi.
tion of this substrate using n-BuLi at 0 °C, followed by
treatment with carbon dioxide, resulted in carboxylation
Key words: N-[2-(4-methoxyphenyl)ethyl]pivalamide,
lithiation, synthesis, electrophile, dilithium intermediate
directed
ortho to the pivaloylaminomethyl group in 64% yield.10
Recently, we have been interested in regioselective lithia-
tion and substitution of phenethylamine derivatives and
found that direct lithiation of ring-unsubstituted acyl de-
rivatives occurred at the α-position.11 Simig and Schlosser
also reported that lithiation of N-2-[(4-methoxyphe-
nyl)ethyl]pivalamide (1) using t-BuLi at –75 °C to –50
°C, followed by treatment with carbon dioxide, resulted in
carboxylation at the CH2 next to the 4-methoxyphenyl
ring (α-lithiation) to give 2 in 79% yield (Scheme 1).12 We
wished to investigate the possibility of ring lithiation of
N-[2-(4-methoxyphenyl)ethyl]pivalamide (1), notwith-
standing that lithiation at this site was not reported at all
under the conditions used by Simig and Schlosser.12 We
have therefore investigated lithiation under other condi-
tions and now report that we have been able to establish
conditions for a high-yielding and general ring-substitu-
tion process.
Phenylethylamine derivatives, especially those containing
oxygen substituents on the phenyl ring (which includes
many biologically active compounds such as dopamine,
adrenaline, and mescaline), represent a hugely important
class of chemicals of interest to both industry and aca-
deme, and selective methods for their synthesis are of con-
siderable interest. Organolithium reagents play an
important role in the development of clean and environ-
mentally friendly processes for the regioselective produc-
tion of specific products.2,3 For example, lithiation of
aromatic compounds often takes place proximal to a di-
recting metalating group (DMG), which typically possess
an oxygen or nitrogen atom.4 Use of such DMG to facili-
tate lithiation, followed by reactions of the organolithium
intermediates obtained in situ with electrophiles, has
found wide application in a variety of synthetic transfor-
mations to produce substituted aromatics or heterocy-
cles.5,6 This approach is one of the most efficient for the
synthesis of substituted and/or modified derivatives,
which sometimes might be difficult to produce by other
routes.5,6
Initially, 1 was lithiated with t-BuLi (3 mol equiv) under
conditions similar to those used by Schlosser,12 followed
by reaction with benzophenone (1.4 mol equiv). The
crude product was purified by column chromatography to
give residual 1 (30%) and a new product, N-[3-hydroxy-
2-(4-methoxyphenyl)-3,3-diphenylpropyl]pivalamide (3;
Figure 1), obtained in 58% yield. Compound 3 was clearly
obtained via the intermediacy of dilithium species 4 (Fig-
ure 1), which was in accord with the results reported by
Schlosser.12
In connection with other work on the use of lithium re-
agents in organic synthesis,7 we have recently reported a
detailed study for the regioselective lithiation and substi-
tution of various substituted benzylamines.8,9 Sometimes
different products were formed, depending on the nature
of the lithiating agent or reaction conditions. We found,
A reaction carried out with n-BuLi under the same condi-
tions as were used with t-BuLi resulted in the starting ma-
CO2H
1) t-BuLi (3.0 equiv), THF
NHCOt-Bu
NHCOt-Bu
–75 to –50 °C, 3 h
2) CO2
3) dil. HCl
MeO
MeO
1
2 (79%)
Scheme 1 Lithiation of 1 followed by reaction with CO2 as reported by Schlosser12
SYNLETT 2013, 24, 0117–0119
Advanced online publication: 11.12.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317859; Art ID: ST-2012-D0962-L
© Georg Thieme Verlag Stuttgart · New York

118
K. Smith et al.
LETTER
the crude products were purified by column chromatogra-
phy (silica gel; Et2O–hexane = 1:1) to give the corre-
sponding substituted products 7–13 in 80–98% yields
(Table 1).
OH
Ph
Li
Ph
N
t-Bu
NHCOt-Bu
OLi
MeO
MeO
Clearly, the procedure outlined in Scheme 3 represents a
simple, efficient, and high-yielding route for substitution
of N-[2-(4-methoxyphenyl)ethyl]pivalamide (1) ortho to
the pivaloylaminoethyl group. However, it was not clear
why lithiation of 1 with t-BuLi at –75 °C to –50 °C gave
side-chain substitution, while lithiation with n-BuLi at
–20 °C to 0 °C gave ring substitution. One possibility was
that at low temperature the lithiation step was under kinet-
ic control, leading to the intermediate 4, with only the
t-BuLi sufficiently reactive to effect the lithiation under
such conditions, but that at higher temperature the organ-
olithium intermediate 4 was capable of isomerization to 6,
so that reactions conducted at the higher temperature were
under thermodynamic control. In order to test this possi-
bility, the reaction of 1 was initially carried out at –75 °C
to –50 °C with t-BuLi (3.0 mol equiv) for three hours
(conditions previously shown to produce 4), and the mix-
ture was then warmed to 0 °C and maintained for a further
two hours, after which benzophenone (1.4 mol equiv) was
added. The cooling bath was removed, and the mixture
was stirred for two hours while warming to room temper-
ature. Purification of the crude product by column chro-
matography gave 7 in 82% yield along with residual 1
(14%). This finding clearly indicated that the dilithium re-
agent 6 (Scheme 2) is thermodynamically more stable
than the dilithium reagent 4 (Figure 1) at higher tempera-
ture.
3 (58%)
4
Figure 1 Structures of compound 3 and dilithium intermediate 4
terial 1 being recovered quantitatively, indicating that
no C-lithiation had taken place, but lithiation of 1 with
n-BuLi (3.0 mol equiv) at –20 °C to 0 °C over two hours,
followed by treatment with benzophenone gave a new
compound, shown by its spectral properties13,14 to be 7
(Scheme 2), isolated in 92% yield. This suggested that
lithiation took place on the ring and that lithium reagents
5 and 6 were produced in situ (Scheme 2).
NHCOt-Bu
n-BuLi, THF
–20 to 0 °C
N
t-Bu
OLi
MeO
MeO
MeO
1
5
n-BuLi, THF
–20 to 0 °C
NHCOt-Bu
1) Ph2CO
0 °C to r.t., 2 h
2) aq NH4Cl
N
t-Bu
OH
Ph
OLi
Ph
7 (92%)
MeO
Li
6
Scheme 2 Lithiation of 1 with n-BuLi followed by reactions with
benzophenone
The latter reaction clearly had potential as a synthetic
method and therefore the same lithiation procedure was
used for reactions with a range of different electrophiles
(Scheme 3). Following workup of the reaction mixtures
In conclusion, N-[2-(4-methoxyphenyl)ethyl]pivalamide
(1) undergoes lithiation with n-BuLi at 0 °C, followed by
treatment with various electrophiles, to give high yields of
the corresponding substituted products having the substit-
uent ortho to the pivaloylaminoethyl group. This contrasts
sharply with earlier results using t-BuLi at lower temper-
ature, which gave α-substitution. The variation arises be-
cause the dilithium reagent 4, formed at low temperature
with t-BuLi, is less stable than dilithium reagent 6, to
which it isomerizes at 0 °C.
Table 1 Synthesis of Products 7–13 According to Scheme 3
Product Electrophile
E
Yield (%)a
7
8
Ph2CO
Ph2C(OH)
92
88
95
80
90
98
89
(CH2)5CO
EtCOMe
(CH2)5C(OH)
EtC(OH)Me
9
Acknowledgment
10
11
12
13
4-MeOC6H4CHO
4-MeOC6H4CH(OH)
We thank Cardiff University and the Saudi Government for finan-
cial support.
4-Me2NC6H4CHO 4-Me2NC6H4CH(OH)
Me2NCHO
I2
CHO
I
References and Notes
(1) Permanent address: G. A. El-Hiti, Department of Chemistry,
Faculty of Science, Tanta University, Tanta 31527, Egypt.
a Yield of isolated product after purification by flash column chroma-
tography.
1) n-BuLi (3.0 equiv), THF
NHCOt-Bu
NHCOt-Bu
–20 to 0 °C, 2 h
2) electrophile (1.4 equiv)
THF, 0 °C to r.t., 2 h
3) aq NH4Cl
MeO
E
MeO
7–13 (80–98%)
1
Scheme 3 Lithiation of 1 with n-BuLi followed by reactions with electrophiles
Synlett 2013, 24, 117–119
© Georg Thieme Verlag Stuttgart · New York

LETTER
Lithiation of N-[2-(4-Methoxyphenyl)ethyl]pivalamide
119
(2) See, for example: (a) Clayden, J. Organolithiums:
Selectivity for Synthesis; Pergamon: Oxford, 2002.
(b) Schlosser, M. Organometallics in Synthesis, 2nd ed.;
Wiley: Chichester, 2002, 1–352. (c) Capriati, V.; Florio, S.;
Salomone, A. Top. Stereochem. 2010, 26, 135. (d) Coldham,
I.; Sheikh, N. S. Top. Stereochem. 2010, 26, 253.
2006, 62, 6036. (c) Luisi, R.; Capriati, V.; Florio, S.; Musio,
B. Org. Lett. 2007, 9, 1263. (d) Clayden, J.; Hennecke, U.
Org. Lett. 2008, 10, 3567. (e) McLaughlin, M.;
Marcantonio, K.; Chen, C.; Davies, I. W. J. Org. Chem.
2008, 73, 4309. (f) Capriati, V.; Florio, S.; Luisi, R.;
Mazzanti, A.; Musio, B. J. Org. Chem. 2008, 73, 3197.
(g) Affortunato, F.; Florio, S.; Luisi, R.; Musio, B. J. Org.
Chem. 2008, 73, 9214. (h) Musio, B.; Clarkson, G. J.;
Shipman, M.; Florio, S.; Luisi, R. Org. Lett. 2009, 11, 325.
(i) Clayton, J.; Clayden, J. Tetrahedron Lett. 2011, 52, 2436.
(j) Ibrahim, N.; Chevot, F.; Legraverend, M. Tetrahedron
Lett. 2011, 52, 305.
(3) See, for example: (a) Beak, P.; Snieckus, V. Acc. Chem. Res.
1982, 15, 306. (b) Nájera, C.; Sansano, J. M.; Yus, M.
Tetrahedron 2003, 59, 9255. (c) Whisler, M. C.; MacNeil,
S.; Snieckus, V.; Beak, P. Angew. Chem. Int. Ed. 2004, 43,
2206. (d) Chadwick, S. T.; Ramirez, A.; Gupta, L.; Collum,
D. B. J. Am. Chem. Soc. 2007, 129, 2259. (e) Dyke, A. M.;
Gill, D. M.; Harvey, J. N.; Hester, A. J.; Lloyd-Jones, G. C.;
Muñoz, M. P.; Shepperson, I. R. Angew. Chem. Int. Ed.
2008, 47, 5067. (f) Coldham, I.; Raimbault, S.; Chovatia, P.
T.; Patel, J. J.; Leonori, D.; Sheikh, N. S.; Whittaker, D. T.
E. Chem. Commun. 2008, 4174. (g) Coldham, I.; Leonori,
D.; Beng, T. K.; Gawley, R. E. Chem. Commun. 2009, 5239.
(h) Coldham, I.; Raimbault, S.; Whittaker, D. T. E.;
Chovatia, P. T.; Leonori, D.; Patel, J. J.; Sheikh, N. S. Chem.
Eur. J. 2010, 16, 4082. (i) Robinson, S. P.; Sheikh, N. S.;
Baxter Carl, A.; Coldham, I. Tetrahedron Lett. 2010, 51,
3642. (j) Guerrand, H. D. S.; Adams, H.; Coldham, I. Org.
Biomol. Chem. 2011, 9, 7921. (k) Thompson, M. J.; Louth,
J. C.; Little, S. M.; Jackson, M. P.; Boursereau, Y.; Chen, B.;
Coldham, I. ChemMedChem 2012, 7, 578. (l) Sheikh, N. S.;
Leonori, D.; Barker, G.; Firth, J. D.; Campos, K. R.; Meijer,
A. J. H. M.; O’Brien, P.; Coldham, I. J. Am. Chem. Soc.
2012, 134, 5300.
(7) See, for example: (a) Smith, K.; El-Hiti, G. A.; Abdo, M. A.;
Abdel-Megeed, M. F. J. Chem. Soc., Perkin Trans. 1 1995,
1029. (b) Smith, K.; El-Hiti, G. A.; Abdel-Megeed, M. F.;
Abdo, M. A. J. Org. Chem. 1996, 61, 647. (c) Smith, K.; El-
Hiti, G. A.; Abdel-Megeed, M. F.; Abdo, M. A. J. Org.
Chem. 1996, 61, 656. (d) Smith, K.; El-Hiti, G. A.;
Pritchard, G. J.; Hamilton, A. J. Chem. Soc., Perkin Trans. 1
1999, 2299. (e) Smith, K.; El-Hiti, G. A.; Shukla, A. P. J.
Chem. Soc., Perkin Trans. 1 1999, 2305. (f) Smith, K.; El-
Hiti, G. A.; Hawes, A. C. Synthesis 2003, 2047. (g) Smith,
K.; El-Hiti, G. A.; Mahgoub, S. A. Synthesis 2003, 2345.
(h) El-Hiti, G. A. Synthesis 2003, 2799. (i) Smith, K.; El-
Hiti, G. A.; Abdel-Megeed, M. F. Synthesis 2004, 2121.
(j) El-Hiti, G. A. Synthesis 2004, 363. (k) Smith, K.; El-Hiti,
G. A.; Hegazy, A. S. Synthesis 2005, 2951. (l) Smith, K.;
Barratt, M. L. J. Org. Chem. 2007, 72, 1031.
(8) (a) Smith, K.; El-Hiti, G. A.; Hegazy, A. S. Synlett 2009,
2242. (b) Smith, K.; El-Hiti, G. A.; Hegazy, A. S.; Fekri, A.;
Kariuki, B. M. ARKIVOC 2009, (xiv), 266.
(9) (a) Smith, K.; El-Hiti, G. A.; Hegazy, A. S. Chem. Commun.
2010, 46, 2790. (b) Smith, K.; El-Hiti, G. A.; Hegazy, A. S.;
Fekri, A. Heterocycles 2010, 80, 941. (c) Smith, K.; El-Hiti,
G. A.; Hegazy, A. S. Synthesis 2010, 1371. (d) Smith, K.; El-
Hiti, G. A.; Hegazy, A. S.; Kariuki, B. Beilstein J. Org.
Chem. 2011, 7, 1219.
(4) See, for example: (a) Beak, P.; Zajdel, W. J.; Reitz, D. B.
Chem. Rev. 1984, 84, 471. (b) Snieckus, V. Chem. Rev.
1990, 90, 879. (c) El-Hiti, G. A. Heterocycles 2000, 53,
1839. (d) Turck, A.; Plé, N.; Mongin, F.; Quéguiner, G.
Tetrahedron 2001, 57, 4489. (e) Anctil, E. J.-G.; Snieckus,
V. J. Organomet. Chem. 2002, 653, 150. (f) Smith, K.; El-
Hiti, G. A. Curr. Org. Synth. 2004, 1, 253. (g) Chinchilla, R.;
Nájera, C.; Yus, M. Chem. Rev. 2004, 104, 2667.
(h) Schlosser, M. Angew. Chem. Int. Ed. 2005, 44, 376.
(i) Foubelo, F.; Yus, M. Curr. Org. Chem. 2005, 9, 459.
(j) Rathman, T. L.; Bailey, W. F. Org. Process Res. Dev.
2009, 13, 144. (k) Houlden, C. E.; Lloyd-Jones, G. C.;
Booker-Milburn, K. I. Org. Lett. 2010, 12, 3090. (l) Page,
A.; Clayden, J. Beilstein J. Org. Chem. 2011, 7, 1327.
(m) El-Hiti, G. A.; Hegazy, A. S.; Alotaibi, M. H.; Ajarim,
M. D. ARKIVOC 2012, (vii), 35.
(10) Simig, G.; Schlosser, M. Tetrahedron Lett. 1988, 29, 4277.
(11) Smith, K.; El-Hiti, G. A.; Alshammari, M. B. Synthesis
2012, 44, 2013.
(12) Simig, G.; Schlosser, M. Tetrahedron Lett. 1991, 32, 1963.
(13) Assignments of signals are based on integration values,
coupling patterns, and expected chemical shifts and have not
been rigorously confirmed. Signals with similar
characteristics might be interchanged.
(5) Examples for substituted benzenes: (a) Clayden, J.; Turner,
H.; Pickworth, M.; Adler, T. Org. Lett. 2005, 7, 3147.
(b) Clayden, J.; Dufour, J. Tetrahedron Lett. 2006, 47, 6945.
(c) Burgos, P. O.; Fernández, I.; Iglesias, M. J.; García-
Granda, S.; Ortiz, F. L. Org. Lett. 2008, 10, 537.
(14) Analytical Data for 7
White solid (0.32 g, 92%); mp 179–181 °C. FTIR: νmax
=
3321, 2958, 1627, 1575, 1292, 1243 cm–1. 1H NMR (500
MHz, CDCl3): δ = 7.35–7.26 (m, 11 H, OH and 2 C6H5), 7.16
(d, J = 8.3 Hz, 1 H, H-6 of 4-MeOC6H3), 6.79 (dd, J = 2.8,
8.3 Hz, 1 H, H-5 of 4-MeOC6H3), 6.24 (d, J = 2.8 Hz, 1 H,
H-3 of 4-MeOC6H3), 6.15 (br, exch., 1 H, NH), 3.63 (s, 3 H,
OCH3), 3.37 (app q, J = 7 Hz, 2 H, CH2NH), 2.60 (t, J = 7.2
Hz, 2 H, CH2), 1.11 [s, 9 H, C(CH3)3] ppm. 13C NMR (125
MHz, CDCl3): δ = 178.8 (s, C=O), 156.9 (s, C-4 of
(d) Castanet, A.-S.; Tilly, D.; Véron, J.-B.; Samanta, S. S.;
De , A.; Ganguly, T.; Mortier, J. Tetrahedron 2008, 64,
3331. (e) Michon, C.; Murai, M.; Nakatsu, M.; Uenishi, J.;
Uemura, M. Tetrahedron 2009, 65, 752. (f) Tilly, D.; Fu, J.-
M.; Zhao, B.-P.; Alessi, M.; Catanet, A.-S.; Snieckus, V.;
Mortier, J. Org. Lett. 2010, 12, 68. (g) Slocum, D. W.;
Wang, S.; White, C. B.; Whitley, P. E. Tetrahedron 2010,
66, 4939. (h) Cho, I.; Meimetis, L.; Belding, L.; Katz, M. J.;
Dudding, T.; Britton, R. Beilstein J. Org. Chem. 2011, 7,
1315. (i) Schmid, M.; Waldner, B.; Schnürch, M.;
4-MeOC6H3), 147.1 (s, C-1 of 2 C6H5), 146.6 (s, C-2 of
4-MeOC6H3), 132.8 (d, C-6 of 4-MeOC6H3), 130.7 (s, C-1 of
4-MeOC6H3), 127.9 (d, C-3/C-5 of 2 C6H5), 127.7 (d, C-2/C-
6 of 2 C6H5), 127.2 (d, C-4 of 2 C6H5), 117.1 (d, C-3 of 4-
MeOC6H3), 111.9 (d, C-5 of 4-MeOC6H3), 83.0 (s, COH),
55.0 (q, OCH3), 41.1 (t, CH2NH), 38.4 [s, C(CH3)3], 32.5 (t,
ArCH2), 27.5 [q, C(CH3)3] ppm. MS (EI): m/z (%) = 399 (77)
[M – H2O]+, 298 (99), 285 (90), 261 (33), 239 (10), 222 (26),
209 (31), 193 (73), 165 (53), 152 (13), 105 (48), 83 (100).
HRMS (EI): m/z calcd for C27H29NO2 [M – H2O]+:
Mihovilovic, M. D.; Stanetty, P. Tetrahedron 2011, 67,
2895. (j) Volz, N.; Clayden, J. Angew. Chem. Int. Ed. 2011,
50, 12148.
(6) Examples for substituted heterocycles: (a) Robert, N.;
Bonneau, A.-L.; Hoarau, C.; Marsais, F. Org. Lett. 2006, 8,
6071. (b) Comoy, C.; Banaszak, E.; Fort, Y. Tetrahedron
399.2198; found: 399.2187.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 117–119

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