Yb(OTf)3-catalyzed one-pot three component synthesis for tertiary amines

Full text of DOI:10.1002/bkcs.10342

Note
DOI: 10.1002/bkcs.10342
BULLETIN OF THE
B. S. Lee et al.
KOREAN CHEMICAL SOCIETY
Yb(OTf)3-catalyzed One-Pot Three Component Synthesis for Tertiary
Amines
*
Bum Seok Lee, Ji Hye Kim, Tae Kyu Nam, and Doo Ok Jang
Department of Chemistry, Yonsei University, Wonju 220-710, Republic of Korea.
*E-mail: dojang@yonsei.ac.kr
Received January 10, 2015, Accepted March 12, 2015, Published online June 25, 2015
Keywords: Tertiary amine, Aldehyde, One-pot reaction, Hexamethyldisilazane, Reductive amination
Tertiary amine functionality is found in many natural bioac-
tive products such as alkaloids, amino acids, nucleic acids,
pharmaceuticals, and agrochemicals.1 Tertiary amines have
also been used as building blocks for nitrogen-containing
organic compounds and synthetic polymers.
This one-pot reductive amination reaction offers mild, effi-
cient reaction conditions to result in high yields of tertiary
amines. Due to its high reactivity, easy handling, and inertness
toward air and water, Yb(OTf )3 is an efficient Lewis acid cat-
alyst in organic transformations.12
N-Alkylation of amines with alkyl halides has been widely
used.2 However, such alkylation reactions lack chemoselec-
tivity and result in over-alkylated products.
Transition metal complex-catalyzed alkylation of ammonia
or amines with alcohols produces amines via alcohol oxida-
tion, imine formation, and imine reduction.3 Transition metal
catalyzed reactions require high catalyst loadings and harsh
reaction conditions.
Reactions of carbonyl compounds and HMDS without a
reducing reagent at high temperature gave the condensation
product N,N0-bis(phenylmethylidene)phenylmethanediamine
(Scheme 1).13 We hypothesized that iminium reaction inter-
mediates might be reduced using a suitable reducing agent
to produce amines.
Prevention of the competitive reduction of parent carbonyl
compounds is of great importance for direct reductive amina-
tion of carbonyl compounds. The reducing agent should favor
reaction with the iminium intermediate over parent carbonyl
compounds. Several reducing reagents were screened to find
a suitable reducing agent for the reaction (Table 1). Benzalde-
hyde was chosen as a model compound. The reaction of benz-
aldehyde (1 equiv) with HMDS (1.5 equiv) and NaBH3CN (1
equiv) in the presence of Yb(OTf )3 (0.1 equiv) in CH2Cl2 was
performed at room temperature (entry 1). This reaction
afforded the expected tertiary amine 2a in 68% yield without
reduced product of the parent carbonyl compound, benzyl
alcohol, 3a. The same reaction using NaBH(OAc)3 instead
of NaBH3CN resulted in lower yield of 2a (entry 2 ). These
two borohydrides showed high chemoselectivity for the imi-
nium intermediate over the carbonyl compound. Reactions
with NaBH4 orBH3 producedthereduced product ofaldehyde
The reductive amination of aldehydes and ketones with
nitrogen sources such as ammonia, urea, ammonium salts,
and amines in the presence of a reducing agent is a powerful
tool for synthesizing structurally diverse amines.4 Practically,
direct amination of carbonyl compounds is attractive because
there is no need to isolate unstable iminium intermediates.
This one-pot procedure offers operational simplicity and
avoids thepreparationofunstable iminium intermediates. Cat-
alytic hydrogenation and metal hydrides are the most com-
monly used reducing agents for iminium intermediates.5
Catalytic hydrogenation is limited due to low tolerance of
functional groups such as carbon–carbon multiple bonds,
nitro, and cyanide. Borohydride derivatives such as
NaBH4,6 NaBH3CN,7 NaBH(OAc)3,8 and borane9 are also
commonly used as reducing agents in the direct reductive ami-
nation of carbonyl compounds. Among these, NaBH3CN and
NaBH(OAc)3 show high chemoselectivity for iminium inter-
mediates over the parent carbonyl compounds with high func-
tional group tolerance. However, a large excess of amine is
needed to prohibit the competitive reduction of parent car-
bonyl compounds.
Hexamethyldisilazane (HMDS) is one of the most widely
used reagents for silylation of hydroxyl groups.10 It is cheap,
stable, commercially available, and easy to handle. HMDS has
also been employed in organic synthesis as a nitrogen source
instead of harmful and odorous ammonia.11
We report a direct reductive amination protocol for the syn-
thesis of tertiary amines employing HMDS as a nitrogen
source in the presence of Yb(OTf )3 at room temperature.
Scheme 1. Reaction of arylaldehyde with HMDS in the presence or
absence of a reducing reagent.
Bull. Korean Chem. Soc. 2015, Vol. 36, 1912–1915
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Wiley Online Library
1912

BULLETIN OF THE
Note
KOREAN CHEMICAL SOCIETY
3a with low yields of tertiary amine 2a (entries 3 and 4).
Silanes were not active reducing agents for the reaction
(entries 5 and 6).4,14
With optimal reaction conditions assessed, the scope and
limitations of the present reaction were investigated. Results
are summarized in Table 4. Aromatic aldehydes containing
electron-withdrawing substituents efficiently proceeded to
afford the corresponding tertiary amines in high yields
(83–85%) regardless of the substituent position (entries
1–6). For p-methoxybenzaldehyde, the reaction was sluggish
with a low yield of the corresponding tertiary amine (entry 7).
This might be attributed to the strong electron-donating prop-
erty of the methoxy group.13b The proposed mechanism in
Scheme 2 implies that electron-rich aldehydes retard nucleo-
philic addition to the carbonyl group to give condensation pro-
ducts. With conversion of both cyclic and acyclic aliphatic
aldehydes to tertiary amines, the corresponding tertiary
amines were obtained in high yields (entries 8–11). 2-
Methylbutanal (1l) gave a lower yield, which is attributed to
Next, solvent effects on the reaction were examined
(Table 2). Reactions inacetonitrile proceededwith ahigh yield
of tertiary amine 2a without reduced product 3a (entry 1). In
tetrahydrofuran (THF), the reduced productwas obtained with
decreased yield of tertiary amine (entry 2). A reaction in
EtOAc gave low yield of the tertiary amine along with the
reduced product. Reactions in CH3Cl and toluene were very
sluggish. The reactions were incomplete even for prolonged
reaction times, with poor yields of the desired product.
Further optimization was performed by varying the ratio of
reagents (Table 3). A reaction with 0.2 equiv of HMDS pro-
duced a large amount of the reduced product 3a (entry 1).
Reactions with 0.3 equiv of HMDS produced tertiary amine
2a without the formation of reduced product 3a (entries
2–5). Yields were decreased with more than 0.3 equiv of
HMDS, although the reaction took place faster (entries
3–5). The aldehyde to HMDS ratio that gave the best result
was 1:0.3 (entry 2). The present reaction did not require a large
amount of carbonyl compounds to prevent reduction of the
parent carbonyl compounds.14a
Table 3. Optimization of reaction conditions with varied ratios of
reagents.a
Table 1. Screening reducing agents for synthesis of tertiary amine
2a.a
Entry
HMDS (equiv)
Time (h)
2a (%)
3a (%)
1
2
3
4
5
0.2
0.3
0.5
1
72
72
24
24
24
64
83
73
72
69
21
0
0
0
0
2
a Isolated yield.
Entry Reducing agent Time (h) 2a (%) 3a (%) 1a (%)
1
2
3
4
5
6
NaBH3CN
NaBH(OAc)3
NaBH4
BH3∙THF
PhSiH3
96
72
24
96
96
96
68
21
10
0
0
0
0
0
51
33
0
0
0
0
30
100
100
Table 4. Synthesis of various tertiary amines.a
Ph2SiH2
0
a Isolated yield.
Entry
R
Time (h) Product Yield (%)
Table 2. Solvent effects on reductive amination of 1a.a
1
2
3
4
5
6
7
8
p-F-C6H4-, 1b
m-F-C6H4-, 1c
o-F-C6H4-, 1d
p-Cl-C6H4-, 1e
o-Cl-C6H4-, 1f
o-Br-C6H4-, 1g
p-MeO-C6H4-, 1h
PhCH2CH2-, 1i
n-Heptyl-, 1j
24
24
24
24
48
48
120
48
48
48
72
2b
2c
2d
2e
85
85
82
83
82
83
32
72
73
86
32
2f
2g
2h
2i
Entry
Solvent
Time (h)
2a (%)
3a (%)
1a (%)
1
2
3
4
5
MeCN
THF
EtOAc
CHCl3
Toluene
24
72
96
96
129
70
65
45
23
22
0
10
14
14
11
0
0
0
29
36
9
10
11
2j
Cyclohexyl-, 1k
CH3CH2(CH3)CH-, 1l
3bb
3cb
a Isolated yield.
a Isolated yield.
b The corresponding alcohol.
Bull. Korean Chem. Soc. 2015, Vol. 36, 1912–1915
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 1913

BULLETIN OF THE
Note
KOREAN CHEMICAL SOCIETY
mmol) in acetonitrile (2 mL), HMDS (44 mg, 0.27 mmol) and
NaBH3CN (0.8 mL, 1 M solution in THF) were added under
argon. The reaction was stirred at room temperature until com-
pletion (monitored with thin-layer chromatography). After
reaction completion, the volatile materials were removed in
vacuum. The residue was dissolved in CH2Cl2, washed with
water, and dried with anhydrous MgSO4. After filtration
and concentration, the residue was purified with silica gel col-
umn chromatography to give tertiary amines. For 2a: 1H NMR
(400 MHz, CDCl3) δ 3.51 (s, 6H, CH2 ), 7.14–7.20 (m, 3H,
Ar), 7.26 (t, 6H, Ar, J = 7.5 Hz), 7.38 (d, 6H, Ar, J = 7.2 Hz);
13C NMR (100 MHz, CDCl3) δ 58.1, 127.0, 128.4, 128.9,
139.8; MS m/z (relative intensity) 287 (M+, 9), 210 (13),
196 (10), 91 (100).
Acknowledgments. This workwas supportedbythe National
Research Foundation of Korea (NRF-2009-0074839; NRF-
2008-521-C00153).
Scheme 2. Plausible mechanism.
steric hindrance of the substrate (entry 11).13a These results
imply that the reaction is very sensitive to the electronic and
steric effects of the substituent. The reaction did not proceed
at all with acetophenone.
References
1. (a) F. Nador, Y. Moglie, A. Ciolino, A. Pierini, V. Dorn, M. Yus,
F. Alonso, G. Radivoy, Tetrahedron Lett. 2012, 53, 3256; (b)
N. V. Petchkova, K. R. Seddon, Chem. Soc. Rev. 2008, 37,
123; (c) E. Byun, B. Hong, K. A. D. Castro, M. Lim,
H. Rhee, J. Org. Chem. 2007, 72, 9815; (d) S. A. Lawrence,
Amine: Synthesis Properties and Applications, Cambridge
University, Cambridge, 2004; (e) H. Zao, S. Hans,
X. Chemg, D. R. Mootoo, J. Org. Chem. 2001, 66, 1761; (f )
M. A. Toczko, C. H. Heathcock, J. Org. Chem. 2000, 65,
2642; (g) T. Welton, Chem. Rev. 1999, 99, 2071; (h)
S. S. Insaf, D. T. Witiak, Synthesis 1999, 3, 435;
(i) J. P. Wolfe, S. Wagaw, J.-F. Marcoux, S. Buchwald, Acc.
Chem. Res. 1998, 31, 805; (j) A. W. Czarnik, Acc. Chem. Res.
1996, 29, 112; (k) M. S. Gibson, In The Chemistry of the Amino
Group, S. Patai Ed., Wiley-Interscience, New York, 1968, p. 61.
2. (a) K.-I. Fugita, Y. Enoki, R. Yamaguchi, Tetrahedron 2008, 64,
1943; (b) M. H. S. A. Hamid, P. A. Slaford, J. M. J. Williams,
Adv. Synth. Catal. 2007, 349, 1555; (c) D. Hollman,
A. Tillack, R. Jackstell, M. Beller, Chem. Asian J. 2007, 2,
403; (d) R. N. Salvatore, A. S. Nagle, K. W. Jung, J. Org. Chem.
2002, 67, 674; (e) R. N. Salvatore, C. H. Yoon, K. W. Jung, Tet-
rahedron 2001, 57, 7785.
3. (a) T. Suzuki, Chem. Rev. 2011, 111, 1825; (b) R. H. Crabtree,
Organometallics 2011, 30, 17; (c) Y. S. Zhao, S. W. Foo,
S. Saito, Angew. Chem. Int. Ed. 2011, 50, 3006; (d) F. Li,
H. X. Shan, Q. K. Kang, L. Chen, Chem. Commun. 2011, 47,
5058; (e) Y. Shiraishi, Y. Sugano, S. Tanaka, T. Hirai, Angew.
Chem. Int. Ed. 2010, 49, 1656; (f ) A. J. A. Watson,
J. M. J. Williams, Science 2010, 329, 635; (g) G. Guillena,
D. J. Ramón, M. Yus, Chem. Rev. 2010, 110, 1611; (h)
T. D. Nixon, M. K. Whittlesey, J. M. J. Williams, Dalton Trans.
2009, 753; (i) G. Guillena, D. J. Ramón, M. Yus, Angew. Chem.
Int. Ed. Engl. 2007, 46, 2358.
By reviewing the intermediates and previous reports,13
a
plausible mechanism was proposed, as shown in Scheme 2.
The Yb(OTf )3-catalyzed nucleophilic addition of Si–N
bonds to the carbonyl group of the aldehyde occurs twice
to give the 1:1-adduct I and the 1:2-adduct II. This was fol-
lowed by elimination of timetylosilanol (TMSOH) to give
N-benzylidenephenylmethane derivative III. Intermediate III
1
was detected in a small amount and confirmed by H NMR
when R was a p-fluorophenyl group. Intermediate III was
reduced to IV following elimination of TMSOH to give inter-
mediate V, which was detected when R was an o-chlorophenyl
group. Reduction of intermediate V leads to secondary amine
VI. Condensation of VI with an aldehyde and reduction of
the resulting product affords the final product, tertiary amine
VII. Without reducing agents, condensation of intermediate
III with HMDS occurs to give intermediate VIII, which is con-
densedfurtherwithanotheraldehyde.13 EliminationofTMSOH
from intermediate IX affords the final product N,N0-bis(aryl-
methylidene)arylmethanediamine X. Yb(OTf )3 promotes each
addition reaction of a Si–N bond to the carbonyl group.
In summary, a one-pot method for directreductive amination
of aldehydes has been developed to synthesize tertiary amines
using HMDS as a nitrogen source in the presence of Yb(OTf )3.
With a stoichiometric amount of HMDS, the reaction afforded
the desired tertiary amines without competitive reduction of the
parent carbonyl compounds. This reaction offers a convenient
and efficient protocol for synthesizing aromatic and aliphatic
tertiary amines under mild reaction conditions.
4. (a) R. Apodaca, W. Xiao, Org. Lett. 2001, 3, 1745; (b) B. T. Cho,
S. K. Kang, Tetrahedron 2005, 61, 5725.
Experimental
5. (a)M. E. Domine, M.C. Hernandez-Soto, Y. Perez, Catal. Today
2011, 159, 2; (b) A. Robichaud, A. N. Ajjou, Tetrahedron Lett.
2006, 47, 3633; (c) D. Imao, S. Fujihara, T. Yamamoto, T. Ohta,
Typical Procedure forOne-Pot Reductive Amination. Toa
solution ofaldehyde(0.81 mmol)and Yb(OTf )3 (50 mg, 0.08
Bull. Korean Chem. Soc. 2015, Vol. 36, 1912–1915
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 1914

BULLETIN OF THE
Note
KOREAN CHEMICAL SOCIETY
Y. Ito, Tetrahedron 2005, 61, 6988; (d) T. Gross, A. M. Seayad,
10. (a) H. Firouzabadi, N. Iranpoor, S. Farahi, Catal. Commun.
2009, 10, 1547; (b) H. Firouzabadi, N. Iranpoor, S. Farahi, J.
Organomet. Chem. 2009, 694, 3923; (c) H. Firouzabadi,
N. Iranpoor, A. A. Jafari, M. R. Jafari, J. Organomet. Chem.
2008, 693, 2711; (d) H. Firouzabadi, N. Iranpoor, S. Sobhani,
Tetrahedron Lett. 2002, 43, 3653; (e) H. Firouzabadi,
N. Iranpoor, K. Amani, F. Nowrouzi, J. Chem. Soc., Perkin
Trans. 1 2002, 2601.
M. Ahmad, M. Beller, Org. Lett. 2002, 12, 2055; (e)
A. W. Heinen, J. A. Peters, H. VanBekkum, Eur. J. Org. Chem.
2000, 2501; (f ) V. I. Tararov, R. Kadyrov, T. H. Riermeier,
A. Borner, Chem. Commun. 2000, 1867; (g) V. A. Tarasevich,
N. G. Kozlov, Russ. Chem. Rev. 1999, 68, 55.
6. (a) N. U. Kumar, B. S. Reddy, V. P. Teddy, R. Bandichhor, Tet-
rahedron Lett. 2012, 53, 4354; (b) A. Heydari, S. Khaksar,
J. Akbari, M. Esfandyari, M. Pourayoubi, M. Tajbakhsh, Tetra-
hedron Lett. 2007, 48, 1135; (c) I. Saxena, R. Borah, J. C. Sarma,
J. Chem. Soc., Perkin Trans. 1 2000, 503; (d) S. Bhattacharyya,
Synth. Commun. 1997, 27, 4265.
7. (a) R. J. Mattson, K. M. Pham, D. J. Leuck, K. A. Cowen, J. Org.
Chem. 1990, 55, 2552; (b) P. Marchini, G. Liso, A. Reho,
F. Liberatone, F. M. Moracci, J. Org. Chem. 1975, 40, 3453;
(c) C. F. Lane, Synthesis 1975, 135; (d) R. F. Borch,
A. I. Hassid, J. Org. Chem. 1972, 37, 1673; (e) R. F. Borch,
M. D. Bernstein, H. D. Durst, J. Am. Chem. Soc. 1971, 93,
2897; (f ) R. O. Hutchins, N. R. Natale, Org. Prep. Proced.
Int. 1979, 11, 201.
8. (a) H. V. Bailey, W. Heaton, N. Vicker, B. V. L. Potter, Synlett
2006, 2444; (b) M. J. Fray, P. Allen, P. R. Bradley,
C. E. Challenger, M. Closier, T. J. Evans, M. L. Lewis,
J. P. Mathias, C. L. Nichols, Y. M. Po-Ba, H. Snow,
M. H. Stefaniak, H. V. Vuong, Tetrahedron 2006, 62, 6869;
(c) T. J. Reddy, M. Leclair, M. Proulx, Synlett 2005, 583; (d)
S. Xiao, Y. Li, Y. Li, H. Liu, H. Li, J. Zhuang, Y. Liu, F. Lu,
D. Zhang, D. Zhu, Tetrahedron Lett. 2004, 45, 3975; (e)
A. F. Abdel-Magid, K. G. Carson, B. D. Harris,
C. A. Maryanoff, D. Shah, J. Org. Chem. 1996, 61, 3849; (f )
A. F. Abdel-Magid, C. A. Maryanoff, K. G. Carson, Tetrahedron
Lett. 1990, 31, 5595.
11. (a) B.-L. Yang, Z.-T. Weng, S.-J. Yang, S.-K. Tian, Chem. Eur.
J. 2010, 16, 718; (b) S. Sobhani, Z. Tashrifi, Heteroat. Chem.
2009, 20, 109; (c) N. Azizi, F. Rajabi, M. R. Saidi, Tetrahedron
Lett. 2004, 45, 9233; (d) H. Uchida, H. Tanikoshi, S. Nakamura,
P. Y. Reddy, T. Toru, Synlett 2003, 1117; (e) H. Uchida,
T. Shimizu, P. Y. Reddy, S. Nakamura, T. Toru, Synthesis
2003, 1236; (f ) M. R. Saidi, N. Azizi, Molecules 2002, 7, 72.
12. (a) Y. Heo, D. H. Cho, M. K. Mishra, D. O. Jang, Tetrahedron
Lett.2012, 53, 3897, [Corrigendum:TetrahedronLett., 2013, 54,
1899.]; (b) W. Rao, X. Zhang, E. M. L. Sze, P. W. H. Chan, J.
Org. Chem. 2009, 74, 1740; (c) K. Manabe, X. Zhang,
W. T. Teo, P. W. H. Chan, Org. Lett. 2009, 11, 4990; (d)
S. Kobayashi, S. Nagayama, T. Busujima, J. Am. Chem. Soc.
1998, 120, 8287; (e) S. Kobayashi, S. Nagayama, J. Org. Chem.
1997, 62, 232; (f ) S. Kobayashi, Synlett 1994, 689; (g)
S. Kobayashi, I. Hachiya, J. Org. Chem. 1994, 59, 3590.
13. (a)N.Azizi,E.Akbari,A.K.Amiri,M.R.Saidi,TetrahedronLett.
2008, 49, 6682; (b) P. Y. Reddy, M. Shimizu, K. Higashi,
T. Shimizu, T. Toru, ARKIVOC 2001, 111; (c) K. Nishiyama,
M. Saito, M. Oba, Bull. Chem. Soc. Jpn. 1988, 61, 609.
14. (a) R. Cano, M. Yus, D. J. Ramón, Tetrahedron 2011, 67, 8079;
(b)P.Pham, P.Bertus, S. Legoupy,Chem. Commun. 2009, 6207;
(c) B. C. Chen, J. E. Sundeen, P. Guo, M. S. Bednarz, R. Zhao,
Tetrahedron Lett. 2001, 42, 1245; (d) S. Chandrasekhar,
C. R. Reddy, M. Ahmed, Synlett 2000, 1655; (e) Y. Han,
M. Chorev, J. Org. Chem. 1999, 64, 1972.
9. M. Tokizane, K. Sato, Y. Sakami, Y. Imori, C. Matsuo, T. Ohta,
Y. Ito, Synthesis 2010, 36.
Bull. Korean Chem. Soc. 2015, Vol. 36, 1912–1915
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 1915