Thiyl radical mediated racemization of nonactivated aliphatic amines

Article abstract of DOI:10.1021/jo061033l

The racemization of nonactivated aliphatic amines has been mediated with alkanethiols and with methyl thioglycolate in the presence of AIBN. The process involves reversible H-abstraction at the chiral center, in a position α relative to nitrogen, by thiyl radical. The knowledge of the reaction enthalpy is critical to select the appropriate thiol. In the absence of experimental values, theoretical calculations of the α-C-H BDEs and the S-H BDE provide a useful guide.

Full text of DOI:10.1021/jo061033l

Thiyl Radical Mediated Racemization of Nonactivated Aliphatic
Amines
†
†
‡
‡
§
St e´ phanie Escoubet, St e´ phane Gastaldi, Nicolas Vanthuyne, G e´ rard Gil, Didier Siri, and
,
†
Mich e` le P. Bertrand*
Laboratoire de Chimie Mol e´ culaire Organique, UMR 6517 “Chimie, Biologie, et Radicaux Libres”,
Boite 562, UniVersit e´ Paul C e´ zanne, Aix-Marseille III, Facult e´ des Sciences St J e´ r oˆ me, AVenue Escadrille
Normandie-Niemen, 13397 Marseille Cedex 20, France, Laboratoire de St e´ r e´ ochimie Dynamique et
Chiralit e´ , UMR 6180 “Chirotechnologies: Catalyse et Biocatalyse”, UniVersit e´ Paul C e´ zanne,
Aix-Marseille III, Facult e´ des Sciences St J e´ r oˆ me, AVenue Escadrille Normandie-Niemen,
1
3397 Marseille Cedex 20, France, and Laboratoire de Chimie Th e´ orique et Mod e´ lisation Mol e´ culaire,
UMR 6517, UniVersit e´ de ProVence, Facult e´ des Sciences St J e´ r oˆ me, AVenue Escadrille
Normandie-Niemen, 13397 Marseille Cedex 20, France
michele.bertrand@uniV-cezanne.fr
ReceiVed May 22, 2006
The racemization of nonactivated aliphatic amines has been mediated with alkanethiols and with methyl
thioglycolate in the presence of AIBN. The process involves reversible H-abstraction at the chiral center,
in a position R relative to nitrogen, by thiyl radical. The knowledge of the reaction enthalpy is critical
to select the appropriate thiol. In the absence of experimental values, theoretical calculations of the R-C-H
BDEs and the S-H BDE provide a useful guide.
4
The most common ways in industry to prepare enantiomeri-
cally pure compounds remain kinetic resolution and chiral
chromatography of racemic mixtures. The recycling of the
unwanted isomer through racemization is of critical importance
from both an economical and an environmental point of view.
With the exception of amino acids derivatives, the racemization
of amines is generally performed by oxidation-reduction which
methods apply to nonactivated aliphatic amines. The ruthenium-
catalyzed methodology developed by B a¨ ckvall and co-workers2
is an exception. It was recently shown to be compatible with
2
e
concomitant enzymatic resolution.
We have reported that chiral benzylic amines could be
racemized by a free radical process, involving thiyl radical-
mediated reversible H-abstraction at the chiral center in position
1-3
5
can involve a complex multistep process or by base catalysis.
R relative to nitrogen (Scheme 1).
6
Both types of procedures often necessitate rather harsh condi-
tions which may not tolerate other functional groups. Very few
Thiols are very good hydrogen atom donors. Hydrogen
transfers from thiols to carbon-centered radicals have been the
subject of numerous debates and theoretical studies. Most of
7
†
Laboratoire de Chimie Mol e´ culaire Organique, Universit e´ Paul C e´ zanne.
‡
(4) For examples, see: (a) US 6153797, 001128 (990301), BASF A.-
G., Fed. Rep. Ger.; Chem. Abstr. 2000, 132, 236800. (b) US 6160178,
001212 (990503), BASF A.-G., Fed. Rep. Ger.; Chem. Abstr. 2000, 132,
308056. (c) Eur. Pat. Appl. 1215197; Chem. Abstr. 2002, 137, 48866. (d)
JP 5401233, 790130 (770629), Sumitomo Chemical Co., Ltd., Japan; Chem.
Abstr. 1979, 91, 20329.
Laboratoire de St e´ r e´ ochimie Dynamique et Chiralit e´ , Universit e´ Paul
C e´ zanne.
§
Laboratoire de Chimie Th e´ orique et Mod e´ lisation Mol e´ culaire, Universit e´
de Provence.
(1) Ebbers, E.; Ariaans, G. J. A.; Houbiers, J. P. M.; Brugginks, A.;
Zwanenburg, B. Tetrahedron 1997, 53, 9417-9476.
(
2) For benzylic amines and a few examples of aliphatic amines, see:
(5) Escoubet, S.; Gastaldi, S.; Vanthuyne, N.; Gil, G.; Siri, D.; Bertrand,
M. P. Eur. J. Org. Chem. 2006, 3242-3250.
(
2
1
a) Samec, J. S. M.; Ell, A. H.; B a¨ ckvall, J.-E. Chem. Commun. 2004, 2748-
749. (b) Samec, J. S. M.; Ell, A. H.; B a¨ ckvall, J.-E. Chem. Eur. J. 2005,
1, 2327-2334. (c) Samec, J. S. M.; Ell, A. H.; B a¨ ckvall, J.-E. Chem.
(6) (a) Crich, D. In Organosulfur chemistry: Synthetic Aspect; Page,
P., Eds.; Academic Press: London, 1995; Chapter 2. (b) Chatgilialoglu,
C.; Bertrand, M. P.; Ferreri, C. In S-Centered Radicals; Alfassi, Z. B., Eds.;
Wiley: New York, 1999; Chapter 11. (c) Bertrand, M. P.; Ferreri, C. In
Radicals in Organic Synthesis; Renaud, P., Sibi, M., Eds.; Wiley-VCH:
New York, 2001; Vol. 2, Chapter 5.5.
Commun. 2004, 2748-2749. (d) P a` mies, O.; Ell, A. H.; Samec, J. S. M.;
Hermanns, N.; B a¨ ckvall, J. E. Tetrahedron Lett. 2002, 43, 4699-4702. (e)
Paetzol, J.; B a¨ ckvall, J. E. J. Am. Chem. Soc. 2005, 127, 17620-17621.
(3) For amino acid derivatives, see also: (a) Schnell, B.; Faber, K.;
Kroutil, W. AdV. Synth. Catal. 2003, 345, 653-666. (b) Yoshimura, T.;
Esaki, N. J. Biosci. Bioeng. 2003, 96, 103-109.
(7) See: K. D. Beare, M. L. Coote, J. Phys. Chem. A 2004, 108, 7211-
7221 and refs. cited therein.
10.1021/jo061033l CCC: $33.50 © 2006 American Chemical Society
7
288
J. Org. Chem. 2006, 71, 7288-7292
Published on Web 08/24/2006

Thiyl Radical Mediated Racemization of Aliphatic Amines
SCHEME 1
them are exothermic processes. However, thiyl radicals are able
8
-11
to abstract hydrogen atoms from electron rich C-H bonds.
Although the importance of hydrogen abstraction by thiyl
12
radicals is now recognized in biological processes, synthetic
applications have not fully been explored yet.8 Our group has
reported that thiyl radicals enable the conversion of allylic
amines into enamines through 1,3-hydrogen shift.13 To the best
of our knowledge, with the exception of an article published
,9
1
1
by Von Sonntag, the few known examples of thiyl radical
promoted epimerization at electron-rich chiral center in position
R relative to an oxygen atom have been reported by Roberts.
In the thiyl radical mediated racemization of amines, both
the forward and the backward hydrogen transfers (Scheme 1)
benefit from favorable polar factors (the strong nucleophilic
character of the carbon-centered radical matches the electrophilic
character of thiyl radical). A balance must be found between
the activation barriers of the forward and backward steps to
ensure the practical efficacy of the process.
FIGURE 1. Structures of amines 1-11.
1
0
TABLE 1. Experimental and Calculated Value of the r-C-H
-
1
BDEs in Methyl Amines (kJ mol
)
H2NCH2-H
MeHNCH2-H
Me2NCH2-H
93 ( 8a
364 ( 8a
a
3
388
3
351 ( 8
b
386b
b
387
89.5c
387.4c
387.8
c
a Reference 16. b G2(MP2) calculations at 298 K, from ref 18. c Average
values from G3 and CBS-(Q) calculations, ref 19.
The information gathered from the experiments performed
5
with benzylic amines can be summarized by the following
has proved useful to rationalize reactivity. The forward hydrogen
transfer in Scheme 1 is generally an endothermic reaction, it is
rate limiting and must not be too slow for the reaction to proceed
in a reasonable time.
statements. The racemization of chiral benzylic amines can be
achieved in the presence of aromatic or aliphatic thiols, but only
the best hydrogen donors enable the racemization to proceed
in the presence of a catalytic amount of thiol. In the case of
primary benzylic amines, the main limitation comes from the
fast competitive oxidation of the carbon-centered radical. Thus,
the backward transfer must be fast enough to compete with
oxidative degradation. The knowledge of the reaction enthalpy
We describe herein the results obtained with (S)-2-amino-4-
phenylbutane (1) and its derivatives (2, 3) that were prepared
from 1 by mono- and double-Michael addition to ethyl acrylate,
respectively (Figure 1). Compound 1 was obtained in 94-99%
ee through the enzymatic resolution of a racemic mixture using
Candida antartica lipase B (Novozym 435) as the catalyst in
14
the presence of ethyl acetate as the acyl donor. The enzymatic
resolution led concomitantly to amide 4 (86% ee). Additional
experiments were performed on the commercially available
amines 9 and 10 and on amine 11.
(
8) (a) Roberts, B. P.; Smits, T. M. Tetrahedron Lett. 2001, 42, 137-
1
3
1
40. (b) Roberts, B. P.; Smits, T. M. Tetrahedron Lett. 2001, 42, 3663-
666. (c) Cai, Y.; Dang, H.-S.; Roberts, B. P. J. Chem. Soc., Perkin Trans.
2002, 22, 2449-2458. (d) Dang, H.-S.; Roberts, B. P.; Sekhon, J.; Smits,
T. Org. Biomol. Chem. 2003, 1, 1330-1341. (e) Dang, H.-S.; Roberts, B.
P.; Tocher, D. A. Org. Biomol. Chem. 2003, 1, 4073-4084. (f) Dang, H.-
S.; Roberts, B. P. J. Chem. Soc., Perkin Trans. 1 1998, 67-75. (g) Dang,
H.-S.; Roberts, B. P. J. Chem. Soc., Perkin Trans. 1 2002, 1161-1170.
Results and Discussion
(
(
9) For a review, see: Roberts, B. P. Chem. Soc. ReV. 1999, 28, 25-35.
10) (a) Cai, Y.; Roberts, B. P. Chem. Commun. 1998, 1145-1146. (b)
Dang, H.-S.; Roberts, B. P. Tetrahedron Lett. 2000, 41, 8595-8599. (c)
Dang, H.-S.; Roberts, B. P.; Tocher, D. A. J. Chem. Soc., Perkin Trans. 1
As stated above, previous investigations of thiyl radical-
mediated racemization of R-branched benzylic amines have
shown that the choice of the appropriate thiol was critical. A
series of values for the R-C-H BDE in aliphatic amines were
available from different sources. They are gathered in Table 1.
It seemed reasonable to assume that the R-C-H bonds should
be stronger in aliphatic amines than in benzylic amines, even
though the few values reported in the literature did not support
2
001, 2452-2461.
11) Akhlaq, M. S.; Schuchmann, H.-P.; Von Sonntag, C. Int. J. Radiat.
Biol. 1987, 51, 91-102.
12) For selected examples, see: (a) Stubbe J.; van der Donk, W. A.
Chem. ReV. 1998, 98, 705-762. (b) Sch o¨ neich, C.; Bonifacic, M.; Dillinger,
U.; Asmus, K.-D. In Sulfur-Centered Reaction Intermediates in Chemistry
and Biology; Chatgilialoglu, C., Asmus, K.-D., Eds.; NATO ASI Series A;
Plenum: New York and London, 1990; Vol. 197, pp 367-376. (c) Griller,
D.; Sim o˜ es, J. A. M.; Wayner, D. D. M. In Sulfur-Centered Reaction
Intermediates in Chemistry and Biology; Chatgilialoglu, C., Asmus, K.-D.,
Eds.; NATO ASI Series A; Plenum: New York and London, 1990; p 37.
(
(
1
5
this assumption. It must be reminded that the influence of
substitution at nitrogen on the R-CH BDE has been controversial
for more than twenty years. It has long been admitted that the
stabilization of R-amino radicals increased with substitution at
nitrogen, i.e., going from primary to tertiary amines. The
stabilization energies relative to methyl radical have been
determined by Burkey et al. by electron impact mass spectrom-
(
(
d) Nauser, T.; Sch o¨ neich, C. J. Am. Chem. Soc. 2003, 125, 2042-2043.
e) Pogocki, D.; Sch o¨ neich, C. Free Rad. Biol. Med. 2001, 31, 98-107. (f)
Porter, N. A.; Wujek, D. G. In ReactiVe Species in Chemistry, Biology,
and Medicine; Quintanilha, A., Eds.; NATO ASI Series A: Life Sciences;
Plenum Press: New York, 1988; Vol. 146. (g) Schwinn, J.; Sprinz, H.;
Leistner, S.; Brede, O.; Naumov, S. J. Phys. Chem. A 2001, 105, 119-
1
27. (h) McGinley, C. M.; Van der Donk, W. A. J. Chem. Soc., Chem.
(14) Gonzalez-Sabin, J.; Gotor, V.; Rebolledo, F. Tetrahedron: Asym-
metry 2002, 13, 1315-1320.
Commun. 2003, 2843-2846. (i) Rauk, A.; Armstrong, D. A. J. Am. Chem.
-
1
Soc. 2000, 122, 4185-4192.
(15) The experimental R-C-H BDE is 90.7 ( 0.4 kcal mol for
-
1
(
13) (a) Bertrand, M. P.; Escoubet, S.; Gastaldi, S.; Timokhin, V. I. Chem.
triethylamine and 89.1 ( 0.6 kcal mol for tribenzylamine according to:
Dombrowski, G. W.; Dinnocenzo, J. P.; Farid, S.; Goodman, J. L.; Gould,
I. R. J. Org. Chem. 1999, 64, 427-431.
Commun. 2002, 216-217. (b) Escoubet, S.; Gastaldi, S.; Timokhin, V. I.;
Bertrand, M. P.; Siri, D. J. Am. Chem. Soc. 2004, 126, 12343-12352.
J. Org. Chem, Vol. 71, No. 19, 2006 7289

Escoubet et al.
TABLE 2. r-C-H BDEs and Energies of the SOMOs of the
Corresponding r-amino Radicals Calculated for Amines 5-7 and
Acetamide 8
SCHEME 2
amine
5
6
7
8
BDE298K (kJ mol-1)
371.9
a
b
372.2
383.1
-4.3
a
b
372.4
384.5
-4.2
a
b
389.1a
382.8
a
R-amino radical SOMO (eV)
-4.5
-5.1
TABLE 3. Calculated and Experimental Values for S-H BDEs
and Energies of the SOMOs of Thiyl Radicals5
,24,13b
a
UB3P86/6-311++G (d,p)//UB3LYP/6-31G(d). b G3B3.
thiol
BuSH
MeO2CCH2SH
S-H BDE (kJ mol-1)
358.2a
364.9
a
etry.16,17 However, the values calculated by Rauk and Armstrong
by the G2(MP2) method did not confirm this trend. According
to these data, the gap between the extreme values would be
359.9b
364.4b
358.5c
363.2
c
d
3
3
60.9
70.7 ( 8.4e
-
1 18
only 2 kJ mol . Recent calculations performed by Guo are
a
RS•SOMO (eV)
-7.3
-7.7
consistent with the latter (Table 1).1
9
a
b
UB3P86/6-311++G(d,p)//UB3LYP/6-31G(d) (this work). G3B3(MP2)
The most recent experimental measurements, reported by
Lalev e´ e et al.,20 have led to the conclusion that substitution at
nitrogen has little influence on the R-C-H BDE. According to
these data, N-alkylation would stabilize the R-amino radical by
c
d
(
ref 5). G3B3 (this work). G3 calculated value at 298 K for n-BuSH
(ref 13b). e Experimental values (ref 24).
-1
less than 4 kJ mol . The additional substituent in tertiary amines
would have a negligible effect on the stability of the carbon-
centered radical.
Since none of the above-mentioned data could be transposed
directly to our series involving the formation of secondary
R-aminoalkyl radicals, R-C-H BDEs calculations were per-
formed, first at the UB3P86/6-311++G(d,p)//UB3LYP/6-31G-
(
1
d) on the series of amines 5-7 (taken as models for compounds
-3) and on acetamide 8 (selected as a model for amide 4)
21
using the Gaussian 03 package. These data are reported in
Table 2. The DFT calculations are known to underestimate the
1
9
BDE values, but they give a reliable trend in the series. Since
it was difficult to appreciate the underestimation in the absence
of experimental values, G3B3 calculations known to give BDE
values very close to the experimental ones,22 were also
performed on amines 5-7.
FIGURE 2. Preferred conformations of amines 5-7.
In agreement with the above-mentioned literature data,1
8-20
the class of the amine has little incidence on the BDE value
-
1
(less than 2 kJ mol between the primary and the tertiary
amine). It is important to note that, in this regard, they differ
from benzylic amines. The R-C-H BDEs of the latter vary
(
16) (a) Burkey, T. J.; Catelhano, A. L.; Griller, D.; Lossing, F. P. J.
-
1
within a larger range (16.4 kJ mol according to G3B3(MP2)
Am. Chem. Soc. 1983, 105, 4701-4703. (b) Griller, D.; Lossing, F. P. J.
5
Am. Chem. Soc. 1981, 103, 1586-1587.
calculations ). Owing to the lack of benzylic stabilization in
(17) The same sequence was reported by Denisov for cyclohexylamines,
the radical, the R-C-H BDEs are stronger in aliphatic amines
cf.: Luo, Y.-R. Handbook of Bond Dissociation Energies in Organic
Compounds; CRC Press: Boca Raton, 2003; p 75 and references cited
therein. The R-CH BDEs given for cyclohexylamine, N-methyl cyclohexy-
lamine, and N,N-dimethylcyclohexylamine are 395.9, 375.9, and 368.6 kJ
-
1
than in benzylic ones by ca. 36 kJ mol in the case of the
5
primary amine (based on G3B3 calculations ). Thus, thiols
having stronger S-H bonds should be needed to achieve the
-
1
mol , respectively.
18) Wayner, D. D. M.; Clark, K. B.; Rauk, A.; Yu, D.; Armstrong, D.
A. J. Am. Chem. Soc. 1997, 119, 8925-8932.
19) Feng, Y.; Wang, J.-T.; Huang, H.; Guo, Q.-X. J. Chem. Comput.
Sci. 2003, 43, 2005-2013.
20) Lalev e´ e, J.; Allonas, X.; Fouassier, J.-P. J. Am. Chem. Soc. 2002,
24, 9613-9621.
21) Gaussian 03, Revision C.02: Frisch, M. J.; Trucks, G. W.; Schlegel,
racemization of aliphatic amines (Scheme 2).
(
-1
As expected, thiocresol (339.6 kJ mol S-H BDE according
5
(
to G3B3(MP2) calculations ) was inefficient to racemize amine
1
. The racemization experiments were performed with oc-
(
23
tanethiol, and with thioglycolic methyl ester (Table 3, n-BuSH
was selected as a model for n-OctSH).
1
(
H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A.,
Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.;
Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.;
Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda,
R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai,
H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.;
Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski,
V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D.
K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui,
Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith,
T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.;
Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople,
J. A. Gaussian, Inc., Wallingford, CT, 2004.
The preferred conformations of the amine and the corre-
sponding R-amino radicals are shown in Figures 2 and 3.
In all cases, the preferred conformation of the amine
corresponds to the antiperiplanar arrangement of the R-C-H
25
bond and the lone pair. According to NBO calculations, the
(23) Cyclohexanethiol and 2-methylundecane-2-thiol have proved as
efficient as octanethiol in additional experiments.
(24) (a) Janousek, B. K.; Reed, K. J.; Braumann, J. I. J. Am. Chem. Soc.
-
1
1980, 102, 3125-3129. (b) A value of 358.4 kJ mol was calculated at
the G3X(MP2)-RAD//MPW1K/6-31+G(d,p) for the S-H BDE in n-PrSH;
-
1
cf. ref 7. (c) A value of 367.0 kJ mol has been used for EtSH; see:
Zavitsas, A. A.; Chatgilialoglu, C. J. Am. Chem. Soc. 1995, 117, 10645-
10654.
(25) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. ReV. 1988, 88,
899-926.
(22) Parkinson, J.; Mayer, P. M.; Radom, L. J. Chem. Soc., Perkin Trans.
2
1999, 2305-2313.
7290 J. Org. Chem., Vol. 71, No. 19, 2006

Thiyl Radical Mediated Racemization of Aliphatic Amines
TABLE 5. Racemization of Amines 1-3, 9, and 10
isolated
time yield (%)
entry amine
RSH (n equiv)
(h)
(NMR)
S/R (ee)
1
2
3
4
5
6
7
8
9
0
1b
n-OctSH (1.2)
n-OctSH (0.2)
2
6
2
3
7
6
6
6
6
6
6
6
6
6
2
2
3
40 (62)
38 (55)
51:49 (2)
b
1
79:21 (58)
b
a
)
1
MeO2CCH2SH (1.2)
MeO2CCH2SH (0.2)
MeO2CCH2SH (0.2)
n-OctSH (1.2)
MeO2CCH2SH (1.2)
n-OctSH (0.2)
MeO2CCH2SH (0.2)
n-OctSH (1.2)
MeO2CCH2SH (1.2)
n-OctSH (0.2)
MeO2CCH2SH (0.2)
MeO2CCH2SH (1.2)
MeO2CCH2SH (1.2)
MeO2CCH2SH (1.2)
MeO2CCH2SH (1.2)
67 (100)
50:50 (0
b
a
1
1
2
2
2
2
3
3
68 (82)
76:24 (52)
50:50 (0)
52:48 (4)
52:48 (4)
54:46 (8)
59:41 (18)
53:47 (6)
53:47 (6)
78:22 (56)
74:26 (52)
93:7 (86)
55:45 (10)
53:47 (6)
51:49 (6)
b
30 (70)
70 (94)
80 (100)
43 (75)
70 (88)
70 (89)
70 (98)
70 (89)
84 (100)
95 (100)
51 (73)
64 (83)
46 (78)
b
b
b
b
b
1
•
•
b
FIGURE 3. Preferred conformations of R-amino radicals 5 -7 .
11
b
12
3
3
4
b
TABLE 4. Hyperconjugative Effects Affecting the r-C-H Bond
Determined by the NBO Method for the Lowest Energy Conformers
of Amines 5-7 (Models for 1-3) and Amide 8 Calculated at the
UB3LYP/6-311++G(d,p)//UB3LYP/6-31+G(d) Level and Bond
Lengths
13
14
15
16
17
c
d
9
e
f
10
11
b
a
b
amine
n f σ*C-H (kJ mol-1)
dC-H (Å
Isolated yield after derivatization with trifluoroacetic anhydride. (ee)0
f
)
94%. c (ee)0 ) 86%. d (ee)0 ) 99%. e (ee)0 ) 95%. (ee)0 ) 99%.
5
6
7
8
30.5
33.1
39.0
8.3
1.106
1.108
1.110
1.009
The secondary amine 2 behaved similarly to 1. It was
racemized by both thiols in the presence of either 1.2 equiv or
0
.2 equiv of thiol (entries 6-9).
overlap between the σ* C-H orbital and the lone pair stabilizes
The tertiary amine was completely racemized in 6 h in the
-
1
the system by ca. 30-39 kJ mol . These effects account for
the variation of the C-H bond length in the series (Table 4).
The planarity of the radical increases in the series going from
the primary to the tertiary amine. The structural parameters are
also reflected in the relative energies of the SOMOs. The carbon-
centered radical corresponding to the tertiary amine is likely to
be more nucleophilic than the secondary and the primary ones
presence of 1.2 equiv of either octanethiol or methyl thiogly-
colate (entries 10, 11). It was only partially racemized after 6
h in the presence of 0.2 equiv of thiol (entries 12, 13).
2
6
According to literature data, acetylation increases the
-1
R-C-H BDE in aliphatic amines by approximately 17 kJ mol
(this was confirmed by theoretical calculations, cf. Table 2).
The chiral center in the acetylated derivative 4 could not be
epimerized whatever thiol was used (n-OctSH or thioglycolic
acid methyl ester under stoichiometric conditions (entry 14)).
The reaction was generalized to primary amines 9, 10 and
11 (entries 15-17).
(Table 2).
The radical reactions were performed under the standard
conditions previously applied to benzylic amines, i.e., a benzene
solution of amine (0.6-0.7 mmol, 0.067 M) containing the
selected thiol (1.2 or 0.2 equiv) was heated at reflux for 2-7 h
in the presence of AIBN (20 mol %). A series of experiments
were carried out over 6 h according to the experimental protocol
The theoretical calculations corroborate quite well the ex-
perimental results and a rationale can be based on the reaction
enthalpy. According to the G3B3 calculations, the R-C-H bonds
5
-1
previously used for benzylic amines, i.e., adding the overall
are stronger than the S-H bonds by 24.3-26 kJ mol in the
-
1
2
0 mol % of AIBN in three equal portions every 2 h. Then,
case of octanethiol and by 19.6-21.3 kJ mol in the case of
methyl thioglycolate. The forward hydrogen transfer is endo-
thermic, it should be rate determining. Although the forward
H-abstraction should go slightly faster in the case of the
thioglycolic ester than in the case of n-OctSH, no significant
impact was noted on the racemization in the presence of a
stoichiometric amount of thiol. In the presence of 0.2 equiv of
thiol, the lower degree of racemization of amine 3 points to the
importance of enthalpy. The backward hydrogen transfer might
be too slow in this case. Additional competitive experiments
were achieved in the presence of a catalytic amount of
octanethiol. They are summarized in Table 6.
reactions were monitored and analyzed by chiral chromatog-
raphy (cf. Supporting Information), adding the whole quantity
of initiator at the beginning of the reaction. Monitoring (ee/
ee0) versus time has shown that in the presence of a stoichio-
metric amount of thiol, racemization was completed within ca.
2
h (cf. Supporting Information; the superimposing of the plots
obtained for the racemization of amines 1 and 3 mediated by
n-OctSH indirectly confirmed the R-CH BDEs calculations).
The results are summarized in Table 5.
In the case of the primary amine the recovery was low, but
the yields in isolated product after an additional step of
trifluoroacetylation reached ca. 70% (entries 1/3, 4). In all cases,
These data confirm the trend revealed in Table 5, i.e., amine
2 is racemized faster than amines 1 and 3 in the presence of a
catalytic amount of thiol. Because calculated R-CH BDEs are
not significantly different, no rationale can be based on the
variation of the reaction enthalpy in the series. The interplay
between slightly different polar and steric effects might be
responsible for the selective of racemization the secondary
amine.
1
H NMR yields were determined by using pentamethyl benzene
as internal standard. Both octanethiol and methyl thioglycolate
were efficient in the presence of a stoichiometric amount of
thiol (entries 1, 3). Amine 1 was also racemized in the presence
of a catalytic amount of thiol (entries 2, 4, 5). However 7 h
were necessary to complete racemization when 0.2 equiv of thiol
were used. It is noteworthy that no oxidative degradation was
detected, contrary to what happened in the case of benzylic
primary amines.5
(26) Cf. ref 17, pp 73 and 85.
J. Org. Chem, Vol. 71, No. 19, 2006 7291

Escoubet et al.
TABLE 6. Variation of ee versus Time in Competitive
Experiments Performed in the Presence of a Catalytic Amount of
n-OctSH
2 h, and it is carried out under mild conditions. Theoretical
calculations have considerable interest since they enable one
to evaluate BDEs that have not been determined yet. Owing to
the strengthening of the R-C-H bond, the thiyl radical-mediated
H-abstraction does not proceed with acetylated primary amines.
Further developments will be reported in due course.
a
b
e
d
c
e
e
competition time (h)
2/1 ee (2) /ee (1)
2/3 ee (2) /ee (3)
0
2
4
6
8
99/99
20/76
0/70
0/68
0/64
99/99
20/86
0/76
0/74
0/72
Experimental Section
a
(0.07M), 2 or 3 (0.07M), n-OctSH (0.2 equiv) in benzene. b NMR
1
General Procedure for the Racemization Experiments. A
0.06 M solution of amine (100 mg) and thiol (1.2 or 0.2 equiv)
in benzene was refluxed for 2 h (stoichiometric condition) or 7
h (catalytic condition) in the presence of AIBN (an overall
quantity of 20 mol % of AIBN was divided into three equal
portions (when reaction time > 2 h) that were added succes-
sively each 2 h). After concentration, the residue was diluted
with HCl (1 M), and the solution was washed with Et2O. The
aqueous phase was basified with saturated sodium carbonate
and extracted with Et2O. The pure amine was isolated after
drying on MgSO4 and concentration.
c
yields after 8 h: 1 (52%), 2 (58%). NMR yields after 8 h: 2 (64%), 3
76%). ee determined by GC. ee determined by HPLC.
d
e
(
It is not possible to estimate the variation in polar effects
contribution in the series. One would expect them to lower the
activation barrier for the hydrogen transfer between the most
•
electrophilic thiyl radical, i.e., MeO2CCH2S and the amine
leading to the most nucleophilic R-amino radical, i.e., 3. Even
without taking into account the possible contribution of steric
effects, the interplay between polar- and enthalpy effects that
are varying within very small ranges is complex, and a
qualitative prediction becomes difficult.
Supporting Information Available: Plots for the variation of
0 0
ee/ee versus time and plots for the variation of ln(ee/ee ) versus
time for the racemization of amines 1 and 3 in the presence of 1.2
equiv of n-OctSH. Experimental procedures. NMR spectra for new
compounds. Computational details. This material is available free
of charge via the Internet at http://pubs.acs.org.
Conclusion
Reversible H-abstraction at the chiral center, in position R
relative to nitrogen, by thiyl radical provides a general method
to racemize aliphatic amines. The reaction can be complete in
JO061033L
7292 J. Org. Chem., Vol. 71, No. 19, 2006