Highly chemoselective Pd-C catalytic hydrodechlorination leading to the highly efficient N-debenzylation of benzylamines

Article abstract of DOI:10.1021/jo9007282

(Equation Presented) In the presence of 1,1,2-trichloroethane, a novel procedure for the Pd-C catalytic N-debenzylation of benzylamines was established. The method proceeded in a synergistic catalytic system and directly gave the products as crystal amine hydrochlorides in practically quantitative yields.

Full text of DOI:10.1021/jo9007282

pubs.acs.org/joc
SCHEME 1
Highly Chemoselective Pd-C Catalytic
Hydrodechlorination Leading to the Highly Efficient
N-Debenzylation of Benzylamines
Chuanjie Cheng, Jianwei Sun, Lixin Xing, Jimin Xu,
Xinyan Wang,* and Yuefei Hu*
Key Laboratory of Bioorganic Phosphorus Chemistry and
Chemical Biology (Ministry of Education), Department of
Chemistry, Tsinghua University, Beijing 100084, P. R. China
wangxinyan@mail.tsinghua.edu.cn; yfh@mail.tsinghua.edu.cn
Received April 6, 2009
Pd-C catalytic hydrogenolysis is one of the most favored
methods for N-debenzylation of benzylamines, characterized by
mild conditions (room temperature and atmospheric pressure),
high conversion, and clean product. However, the method suffers
from poor isolated yields for many biologically important amine
products with low molecular weights and multihydrophilic
groups, because the former are highly volatile and the latter are
water-soluble. One of the best improvements is to convert them
into amine hydrochlorides by treatment with aqueous HCl or
saturated solution of HCl (g) in an anhydrous organic solvent.5,6
In our previous work, the natural product (2S,6R)-dihydropini-
In the presence of 1,1,2-trichloroethane, a novel procedure
for the Pd-C catalytic N-debenzylation of benzylamines
was established. The method proceeded in a synergistic
catalytic system and directly gave the products as crystal
amine hydrochlorides in practically quantitative yields.
dine (2q) was isolated in 25% yield, whereas the crystal 2q HCl
3
was obtained in 79% yield from the same Pd-C catalytic
hydrogenolysis of 1q (Scheme 1).4 However, this improvement
usually was incompatible with many acid-sensitive functional
groups and was associated with tedious operations.
It is well-known that C-Cl bonds in organochlorides can be
cleaved to release HCl in Pd-C catalyzed hydrodechlori-
nation,7 in which a base (inorganic bases or tertiary amines)
usually is employed as both HCl acceptor and reaction promoter.8
N-Debenzylation of benzylamines is a fundamental transfor-
mation in modern organic syntheses. For example, benzyla-
mines are major protective groups for amines in multistep
syntheses, where N-debenzylation is an essential conversion
for the deprotection.1,2 In recent years, many chiral benzyla-
mines served as excellent chiral auxiliaries in asymmetric synth-
eses, in which N-debenzylation is a necessary step to remove the
auxiliary residue from the induced molecules.3,4
(5) For amine products with small molecular weights, see: (a) Evans,
G. B.; Furneaux, R. H.; Greatrex, B.; Murkin, A. S.; Schramm, V. L.; Tyler,
P. C. J. Med. Chem. 2008, 51, 948–956. (b) Davies, S. G.; Garner, A. C.;
Goddard, E. C.; Kruchinin, D.; Roberts, P. M.; Rodriguez-Solla, H.;
Smith, A. D. Chem. Commun. 2006, 2664–2666. (c) Kaur, K.; Aeron, S.;
Bruhaspathy, M.; Shetty, S. J.; Gupta, S.; Hegde, L. H.; Silamkoti, A. D. V.;
Mehta, A.; Chugh, A.; Gupta, J. B.; Sarmaa, P. K. S.; Kumara, N. Bioorg.
Med. Chem. Lett. 2005, 15, 2093–2096. (d) Hulin, B.; Cabral, S.; Lopaze,
M. G.; Van Volkenburg, M. A.; Andrews, K. M.; Parker, J. C. Bioorg. Med.
Chem. Lett. 2005, 15, 4770–4773.
(1) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis,
3rd ed.; John Wiley & Sons, Inc.: New York, 1999.
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Fukuda, Y. J. Med. Chem. 2008, 51, 3238–3249. (b) Gonzlez-Sabn, J.; Gotor,
V.; Rebolledo, F. J. Org. Chem. 2007, 72, 1309–1314. (c) Faler, C. A.; Joulli,
M. M. Org. Lett. 2007, 9, 1987–1990. (d) Arefalk, A.; Larhed, M.; Hallberg,
A. J. Org. Chem. 2005, 70, 938–942. (e) White, K. N.; Konopelski, J. P. Org.
Lett. 2005, 7, 4111–4112. (f) Wang, X. J.; Hart, S. A.; Xu, B.; Mason,
M. D.; Goodell, J. R.; Etzkorn, F. A. J. Org. Chem. 2003, 68, 2343–2349.
(g) Kuehne, M. E.; Cowen, S. D.; Xu, F.; Borman, L. J. Org. Chem. 2001, 66,
5303–5316. (h) Liras, S.; Lynch, C. L.; Fryer, A. M.; Vu, B. T.; Martin, S. F.
J. Am. Chem. Soc. 2001, 123, 5918–5924.
(3) For selected references, see: (a) Resek, J. E. J. Org. Chem. 2008, 73,
9792–9794. (b) Amat, M.; Perez, M.; Minaglia, A. T.; Bosch, J. J. Org. Chem.
2008, 73, 6920–6923. (c) Santarem, M.; Vanucci-Bacque, C.; Lhommet, G.
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Molins, E.; Bosch, J. Angew. Chem., Int. Ed. 2008, 47, 3348–3351. (e) Noel,
(6) For amine products with multihydrophilic groups, see: (a) Pandey,
G.; Bharadwaj, K. C.; Khan, M. I.; Shashidhara, K. S.; Puranik, V. G. Org.
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Biomol. Chem. 2008, 6, 2587–2595. (b) Carreno, M. C.; Hernandez-Torres,
G.; Urbano, A.; Colobert, F. Eur. J. Org. Chem. 2008, 2035–2038. (c) Gelmi,
M. L.; Cattaneo, C.; Pellegrino, S.; Clerici, F.; Montali, M.; Martini, C.
J. Org. Chem. 2007, 72, 9811–9814. (d) Galeazzi, R.; Martelli, G.; Mobbili,
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3257–3260.
(7) (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2002, 102, 4009–
4092. (b) Nishimura, S. Handbook of Heterogeneous Catalytic Hydro-
genation for Organic Synthesis; John Wiley & Sons, Inc.: New York, 2001;
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(8) (a) Xia, C.; Liu, Y.; Xu, J.; Yu, J.; Qin, W.; Liang, X. Catal. Commun.
2009, 10, 456–458. (b) Kume, A.; Monguchi, Y.; Hattori, K.; Nagase, H.;
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NaKano, Y.; Nishijima, W.; Okada, M. Tetrahedron Lett. 2005, 46, 3613–
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R.; Vanucci-Bacque, C.; Fargeau-Bellassoued, M.-C.; Lhommet, G. Eur. J.
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Seth Horne, W.; Joyce, L. A.; Alexander, L. R.; Fleming, W. S.; Hopkins,
E. A.; Gellman, S. H. J. Am. Chem. Soc. 2007, 129, 6050–6055. (g) Amat, M.;
Bassas, O.; Llor, N.; Cantl, M.; Prez, M.; Molins, E.; Bosch, J. Chem.;Eur.
J. 2006, 12, 7872–7881. (h) Fujita, K.-i.; Fujii, T.; Yamaguchi, R. Org. Lett.
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DOI: 10.1021/jo9007282
r
Published on Web 06/17/2009
J. Org. Chem. 2009, 74, 5671–5674 5671
2009 American Chemical Society

Cheng et al.
JOCNote
TABLE 1. Chemoselective Hydrodechlorination of 3a-f
entry
3a-f
1a:3 (equiv)
absorbed H2 (equiv)a
yield of 2a HCI (%)c
3
1
2
3
4
5
6
chlorocyclohexane (3a)
CH3(CH2)4CH2Cl (3b)
CH3CH2CHCl2 (3c)
tBuCH2CHCl2 (3d)
CH3CCl2CH3 (3e)
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1.0 (2 h)
1.0 (2 h)
0d
0d
98
98
98
98
2.0 (60 min)b
2.0 (60 min)b
2.0 (60 min)b
2.0 (60 min)b
CH2ClCHCl2 (3f)
aAbsorption of hydrogen ceased completely. bOne mole of H2 was consumed for normal N-debenzylation and another 1 mol for hydrodechlorination.
cIsolated yield was obtained. dNo 1a was isolated, and 2a was obtained as a single product.
TABLE 2. Highly Efficient N-Debenzylation of 1a in the Presence of 3f
SCHEME 2
1a:3f
(equiv)
absorbed H2
(equiv)a
time
(min)
yield of
2a HCl (%)b
On the basis of the above facts, different chloroalkanes with
higher molecular weights were tested for their chemoselective
hydrodechlorinations by employing N-benzyl-N-hexyl-2,2-di-
methoxyethylamine (1a) as an HCl acceptor. As shown in
Table 1, the monochloroalkanes resisted a catalytic hydrode-
chlorination under the mild conditions. When the mixture of
1a (1.0 equiv), 10% Pd-C (10 wt%), and chlorocyclohexane
(3a, 1.1 equiv) or 1-chlorohexane (3b, 1.1 equiv) was hydro-
genated at room temperature and atmospheric pressure, the
normal hydrogenolysis of 1a occurred quantitatively within 2 h,
entry
3
1
2
3
4
5
1:1.1
0:1
1:5
1:0.6
1:0
2.0
0.0
2.0
1.6
1.0
60
180
60
50
180
98
0
98
58
0c
aAbsorption of hydrogen ceased completely. bIsolated yield was
obtained. cNo 1a was isolate and 2a was obtained as a single product.
Thus, when a tertiary benzylamine is used as a HCl acceptor in a
hydrodechlorination, it should carry out a catalytic hydrogeno-
lysis to directly yield the corresponding amine hydrochloride.
but no expected product 2a HCl was obtained (entries 1 and 2).
3
Luckily, when the geminal dichloroalkanes, such as 1,1-dichlor-
opropane (3c), 1,1-dichloro-3,3-dimethylbutane (3d), 2,2-di-
chloropropane (3e), or 1,1,2-trichloroethane (3f), were tested,
By this strategy, 1q was converted into 2q HCl in 97% yield
3
directly in hydrodechlorination of CH2Cl2 (Scheme 1).4
However, one drawback of this otherwise efficient N-debenzy-
lation is that the hydrogen consumption was unpredictable
because the system pressure was increased rather than decreased
during the hydrogenolysis. Thus, the reaction time was estimated
leading to low efficiency (for example, 48 h for 1q).4 The control
experiments indicated that the drawback was mainly caused by
two factors: (1) the hydrodechlorination of CH2Cl2 is a non-
chemoselective process, which can occur slowly even without
tertiary amine (as a HCl acceptor), and (2) the cleavage of each
C-Cl bond absorbed 1 mol of gaseous H2 and released 2 mol of
gaseous products HCl and CH3Cl.9 Deductively, the drawback
should be overcome by replacement of CH2Cl2 with a suitable
chloroalkane that can take place a chemoselective hydrodechlor-
ination to release 1 mol of HCl and 1 mol of liquid residue.10
However, the investigation showed that no such chloroalkanes
or such chemoselctive hydrodechlorination were reported in the
literature to date.
a crystal product 2a HCl was obtained in 98% yield within
3
60 min (entry 3-6). In each case of 3c-f, the theoretical amount
of hydrogen was absorbed (2.0 mol of H2 was consumed, one
for the normal hydrogenolysis and the other for the hydrode-
chlorination), and a very sharp end-point was observed. Since
the control experiment11 proved that 3f was converted into
ClCH2CH2Cl after the hydrodechlorination, it was confirmed
that the geminal dichloroalkanes underwent a monohydrode-
chlorination. To the best of our knowledge, this is the first
highly chemoselective Pd-C catalyzed monohydrodechlori-
nation of geminal dichloroalkanes.
To explore the application of this chemoselective hydro-
dechlorination to the N-debenzylation of benzylamines, 1,1,
2-trichloroethane (3f) was chosen as a practical HCl donor
because it is a very cheap, commercially available geminal
dichloroalkane. As shown in Table 2, the experimental results
clearly revealed that the chemoselective hydrodechlorination, in
fact, was well controlled by the amount of benzylamine 1a.
There was no hydrodechlorination of 3f in the absence of 1a
(entry 2). When 1:5 (by mole) of 1a:3f was used, no more than
2 mol of hydrogen was absorbed (entry 3). The result in entry 4
proved again that the geminal dichloroalkanes underwent only
(9) Prati, L.; Rossi, M. Appl. Catal., B 1999, 23, 135–142.
(10) Because HCl molecules occupy the Pd-C catalytic sites unreversa-
bly under anhydrous conditions (anhydrous HCl is a strong poison for Pd-C
catalyst) and its amount is not easily controllable, anhydrous gaseous
HCl could not be used for this purpose. See : Nishimura, S. Handbook of
Heterogeneous Catalytic Hydrogenation for Organic Synthesis; John Wiley
& Sons, Inc.: New York, 2001; Chapter 2.
(11) Details are described in Supporting Information.
5672 J. Org. Chem. Vol. 74, No. 15, 2009

Cheng et al.
JOCNote
TABLE 3. N-Debenzylation of 1a-r in the Presence of Geminal Dichloroalkane 3f
a The absorption of hydrogen ceased completely. b The isolated yields were obtained.
a monohydrodechlorination. By using 1:0.6 (by mole) of 1a:3f,
the exact 1.6 mol of hydrogen was absorbed. Additionally, we
also observed that the hydrogenolysis of 1a was accelerated
remarkably by HCl released in situ in the hydrodechlorination
of 3f. For example, the N-debenzylation of 1a took 3 h without
3f (entry 5), whereas the same reaction was accomplished within
60 min by addition of 3f (entries 1 and 3).
Thus, a novel procedure for the N-debenzylation of benzyl-
amines was established, which exhibited high chemoselectivity
and efficiency because it proceeded in a synergistic catalytic
system. As shown in Scheme 2, the hydrodechlorination of 3f
initially was promoted by using 1a as an HCl acceptor. Then,
N-Boc (entry 14), and O-TBS (entry 15) groups stayed intact to
give the corresponding amine hydrochlorides in effectively
quantitative yields. When double the amount of 3f was used,
the substrate 1p was converted automatically into the corre-
sponding dihydrochloride 2p 2HCl (entry 16). However,
although two benzyl groups in 1r were hydrogenolyzed
completely to produce 2r HCl in 99% yield (entry 18), no
3
3
N-debenzylation occurred when the alkyl-substituted secondary
benzylamines were used as substrates. Thus, EtNHBn,
tBuNHBn, and HOCH2CH2NHBn were quantitatively con-
verted into the corresponding hydrochlorides EtNHBn HCl,
tBuNHBn HCl, and HOCH2CH2NHBn HCl. This chemose-
3
3
3
lective hydrogenolysis between tertiary and secondary benzyl-
amines is fully in agreement with those reported in the refer-
ences.12 Under our standard conditions, the N-benzylanilines
could not give the expected N-debenzylated products because the
aromatic ring hydrogenated products were produced. It is
noteworthy that the workup procedure for this method is just
N-debenzylation of 1a HCl was accelerated by HCl to directly
give the corresponding 2a HCl.
3
3
As shown in Table 3, the method showed very general scope
and chemoselectivity. Different substrates 1a-r were N-deben-
zylated smoothly to give the corresponding amine hydrochlor-
ides 2a-r nHCl in excellent yields, whether the N-debenzyled
3
products are a gaseous amine (entry 2), a low-boiling point
amine (entry 3), or highly volatile amines (entries 4, 6, and 7).
There was no loss of enantiomeric excess for the chiral amines
(entries 9 and 17). The acetate moieties (entries 9, 10, and 11) and
the highly acid-sensitive acetal (entries 1 and 12), ketal (entry 13),
ꢀ
ꢀ
ꢀ
(12) For selected references, see (a) Tircso, G.; Benyei, A.; Kiraly, R.;
ꢀ ꢀ
ꢀ
€
Lazar, I.; Pal, R.; Brucher, E. Eur. J. Inorg. Chem. 2007, 701–713. (b) Lee,
J.-D.; Lee, Y. J.; Jeong, H.-J.; Lee, J. S.; Lee, C. H.; Ko, J.; Kang, S. O.
Organometallics 2003, 22, 445–449. (c) Kuehne, M. E.; Cowen, S. D.; Xu, F.;
Borman, L. S. J. Org. Chem. 2001, 66, 5303–5316. (d) Studer, M.; Blaser,
H.-U. J. Mol. Catal. A: Chem. 1996, 112, 437–445.
J. Org. Chem. Vol. 74, No. 15, 2009 5673

Cheng et al.
JOCNote
a simple filtration because all substrates gave their products as
solid crystal amine hydrochlorides.
1HNMR(D2O): δ3.68 (t, J= 4.1 Hz, 4H), 3.22 (t, J= 5.5 Hz, 4H),
1.43 (s, 9H). 13C NMR (D2O): δ 155.8, 82.8, 43.1 (2C), 40.4 (2C),
27.6 (3C). MS m/z (%): 186 (M-HCl, 15.6), 56 (100). Anal. Calcd
for C9H19ClN2O2: C, 48.54; H, 8.60; N, 12.58. Found: C, 48.56;
H, 8.57; N, 12.62.
In summary, a novel method of Pd-C catalyzed N-deben-
zylation of benzylamine was developed. The method
was characterized by simple addition of a geminal dichloro-
alkane into a conventional hydrogenolysis system and
achieved high efficiency and clean products. The benefits
of this method are 3-fold. First, the poor yield in the
conventional N-debenzylation was overcome completely
and the volatile amines, even the gaseous amines, can be
obtained as their hydrochlorides in practically quantitative
yields. Second, the traditional two steps (Pd-C catalytic
hydrogenolysis and conversion of amine into its hydro-
chloride) are combined into a single easy procedure. Third,
the new N-debenzylation provides a method to prepare
amine hydrochlorides bearing functional groups that might
be unstable to hydrogenolysis conditions employing acidic
media. This method can be expected to replace the conven-
tional catalytic hydrogenolysis to be used widely in asym-
metric syntheses and in natural products syntheses.
Prepation of N-Ethyl-(3-tert-butyldimethyl-silyloxy)-propyla-
mine Hydrochloride (2o HCl). A mixture of 1o (769 mg,
3
2.5 mmol), CH2ClCHCl2 (369 mg, 2.75 mmol), and 10% Pd-C
(76.9 mg) in MeOH (50 mL) was stirred under hydrogen atmo-
sphere until the absorption of hydrogen ceased (70 min) (the
hydrogenation was carried out on an atmospheric pressure
hydrogenator). After the Pd-C catalyst was filtered off, the
solvent was removed by rotary evaporation. The residue was
diluted with dry diethyl ether, and crystalline product 2o HCl
(622 mg, 98%) was collected by filtration: mp 168-170 °C
3
1
(MeOH/Et2O). IR (KBr): ν 2956, 1469, 1256 cm-1. H NMR
(D2O): δ 3.77 (t, J = 5.8 Hz, 2H), 3.09-3.01 (m, 4H), 1.92-1.83
(m, 2H), 1.24 (t, J = 7.5 Hz, 3H), 0.86 (s, 9H), 0.09 (s, 6H). 13
C
NMR (D2O): δ 60.9, 44.8, 42.9, 28.4, 25.6 (3C), 17.8, 10.7, -5.9
(2C). MS (EI): m/z (%) 217 (M-HCl, 4.8), 160 (100). Anal. Calcd
for C11H28ClNOSi: C, 52.04; H, 11.12; N, 5.52. Found: C, 52.02;
H, 11.16; N, 5.50.
The same procedure was used to convert the substrates 1a-r
Experimental Section
efficiently to the corresponding products 2a-r nHCl.
3
Preparation of N-Boc-Piperazine Hydrochloride (2n HCl).
3
A mixture of 1n (691 mg, 2.5 mmol), CH2ClCHCl2 (369 mg,
2.75 mmol), and 10% Pd-C (69.1 mg) in MeOH (50 mL) was
stirred under hydrogen atmosphere until the absorption of hydro-
gen ceased (140 min) (the hydrogenation was carried out on an
atmospheric pressure hydrogenator). After the Pd-C catalyst was
filtered off, the solvent was removed by rotary evaporation. The
residue was diluted with dry diethyl ether, and crystalline product
Acknowledgment. This work was supported by the
CFKSTIP from Ministry of Education of China (706003)
and NNSFC (20672066, 30600779).
Supporting Information Available: Experiments, charac-
terization, and 1H and 13C NMR spectra for all products
2n HCl (545 mg, 98%) was collected by filtration: mp 236-238 °C
2a-r nHCl. This material is available free of charge via the
Internet at http://pubs.acs.org.
3
3
(MeOH/Et2O). IR (KBr): ν2967, 2799, 2732, 2619, 2474, 1695 cm-1
.
5674 J. Org. Chem. Vol. 74, No. 15, 2009