Ruthenium-catalyzed direct amination of alcohols with tertiary amines

Article abstract of DOI:10.1016/j.tetlet.2011.03.084

A highly selective phosphine-based ruthenium catalyst system efficiently catalyzes the direct amination of alcohols with aliphatic tertiary amines, yielding unsymmetric tertiary amines in yields up to 87%. Ligand and solvent both affect the reaction yields significantly. The reaction can be performed with a wide variety of functionalities.

Full text of DOI:10.1016/j.tetlet.2011.03.084

Tetrahedron Letters 52 (2011) 2706–2709
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Tetrahedron Letters
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Ruthenium-catalyzed direct amination of alcohols with tertiary amines
⇑
Jiaying Luo, Mingyue Wu, Fuhong Xiao, Guojun Deng
Key Laboratory for Environmental Friendly Chemistry and Application of Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan 411105, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly selective phosphine-based ruthenium catalyst system efficiently catalyzes the direct amination
of alcohols with aliphatic tertiary amines, yielding unsymmetric tertiary amines in yields up to 87%.
Ligand and solvent both affect the reaction yields significantly. The reaction can be performed with a
wide variety of functionalities.
Received 4 January 2011
Revised 6 March 2011
Accepted 17 March 2011
Available online 11 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Alcohol
Amination
Ruthenium
Tertiary amine
O
Amines are of great importance as building blocks for pharma-
ceuticals, agrochemicals, dyes, ligands, and material chemistry.1
Thus, the development of versatile and efficient methods for the
synthesis of amines has attracted much attention.2 The best-
known reaction for the alkylation of amines is the nucleophilic
substitution reaction of amines with haloalkanes, although this
procedure can be problematic due to overalkylation and the toxic
nature of many alkyl halides and related alkylating reagent.3 The
reductive amination of ketones and aldehydes with primary and
secondary amines has been used as a useful tool for N-alkylation
of amines. The process generally proceeds in two tandem steps,
condensation between carbonyl compounds and amines to gener-
ate an imine intermediate and reduction of the imine by a reducing
agent (Scheme 1).4 Using this method, secondary and tertiary
amines can be selectively synthesized from primary and secondary
amines, respectively.
Alcohols are cheap and readily available organic compounds and
can be readily oxidized to aldehydes and ketones.5 The use of alco-
hols as starting materials to form C–N bonds is, therefore, poten-
tially atom economical and less hazardous. The alkylation of
amines by alcohols under harsh conditions was reported indepen-
dently by Grigg and Watanable in the early 1980s.6 In recent years,
milder conditions have been achieved by Yamaguchi and co-work-
ers with [Cp⁄IrCl2]2 as catalyst7 and by Beller and co-workers using
Ru3(CO)12 together with bulky phosphines.8 Williams and co-work-
ers developed an efficient [Ru(p-cymene)Cl2]2/phosphine catalyst
system and realized the alkylation of amines and sulfonamides
with alcohols under mild reaction conditions.9 In recent years, var-
R'
R'
1) condensation
2) reduction
+
NH
NH
R
N
Reductive amination
R
R
H
R"
R"
R'
R"
R'
R'
R'
R'
catalyst
Ru
+
+
R
R
N
Borrowing hydrogen
This work
OH
R"
N
R
OH
N
R'
R'
Scheme 1. Tertiary amine formation with amine.
ious amines,10 imines11 and even amides12 can be selectively syn-
thesized from alcohols and primary amines, secondary amines,
and even ammonium or ammonium salts in one-pot. In a typical
process of secondary and tertiary amine synthesis, alcohol was oxi-
dized to aldehyde or ketone which can be condensed with amine to
form an imine intermediate which can be reduced by hydrogen
which was released during alcohol oxidation step and no additional
reducing agent is necessary. The overall process is termed as the
‘borrowing hydrogen’ methodology (Williams and co-workers) or
‘hydrogen autotransfer’ reaction (Yus and co- workers).13,14 In
sharp contrast to amination of alcohols with primary and secondary
amines, little has known for that with tertiary amines.15,16
Recently, we developed a ruthenium-catalyzed tertiary amine
formation from nitroarenes and alcohols via borrowing hydrogen
strategy.17 During the optimization of reaction conditions, we ob-
served a reaction occurred between alcohols and tertiary amines.
This prompted us to investigate the reaction between alcohols and
tertiary amines systematically. Herein, we report an unprecedented
⇑
Corresponding author. Tel.: +86 731 58298601; fax: +86 731 58292251.
E-mail address: gjdeng@xtu.edu.cn (G. Deng).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.084

J. Luo et al. / Tetrahedron Letters 52 (2011) 2706–2709
2707
Table 2
ruthenium-catalyzed direct amination of alcohols with tertiary
amines.
To begin our study, the reaction of commercially available p-
Amination of alcohols with tertiary aminesa
.
RuCl3 3H2O/dppf
RCH2OH
NR'3
RCH2NR'2
(RCH2)2NR'
+
+
chlorobenzene
methylbenzyl alcohol (1a) and tributylamine (2a) was chosen as
a model using RuCl3ꢀ3H2O as a catalyst in chlorobenzene at
145 °C. When 2a was reacted with 3 equiv of 1a in the absence
of any ligand, 35% of desired product was formed as determined
by GC–MS and 1H NMR methods (Table 1, entry 1). Subsequently,
various ligands were investigated for this reaction under an atmo-
sphere of argon (entries 2–8). Moderate yields were obtained when
dppp [1,3-bis(diphenylphosphino)propane] and dppb [1,4-
bis(diphenylphosphino)butane] were used as ligands. The yields
increased when PPh3 and dppe [1,2-bis(diphenylphosphino)eth-
ane] were used. The best yield was obtained when dppf [1,10-
bis(diphenylphosphino)ferrocene] was used as the ligand, and
the desired product was achieved in 92% yield along with 7% bis-
alkylated byproduct (entry 6). PCy3HBF4 is also efficient for this
tranformation. However, only a trace amount of the product was
found when binap [(1,2-bis(diphenylphosphino)-1,10-binaphthyl)]
was used as a ligand. Other ruthenium complexes were also inves-
tigated by using dppf as the ligand and lower yields were obtained
(entries 9–12). The solvent effect on the reaction was also investi-
gated (entries 13–16). Lower yield was achieved when the reaction
was carried out in other solvents. Almost no desired product was
obtained when DMF and DMSO were used as solvents. Interest-
ingly, the bis-alkylated product was the major product when the
reaction was run in no solvent and only 2% of the desired product
was observed (entry 17). Decreasing the reaction temperature de-
creased the product yield (entry 18). The desired product was ob-
tained in 73% yield by using 2 equiv of alcohol (entry 19).
145 o
C
1
2
3
4
Entry
Alcohol(1)
Amine(2)
Yieldb (%)
3
4
OH
1a
1b
1c
1
2
NBu3
NBu3
84
7
9
OH
81
78
OH
3
4
5
6
NBu3
NBu3
NBu3
NBu3
3
9
O
OH
1d
1e
1f
87
76
64
F
OH
Trace
Cl
OH
7
Br
OH
1g
7
NBu3
NBu3
NBu3
NBu3
10
58
75
61
Trace
O2N
OH
OH
1h
1i
8
3
2
4
9
Cl
OH
1j
10
With the optimized conditions in hand, the scope of the reac-
tion with respect to tertiary amines and alcohols was investigated
(Table 2). The nature of the alcohol and amine has great influence
on the results. Benzyl alcohol and 4-methoxybenzyl alcohol re-
acted with tributylamine and gave the desired products in 81%
and 78% yield, respectively (entries 2 and 3). Halogen-substituted
OH
1k
1l
11
12
NBu3
NBu3
63
68
Trace
7
OH
O
1m
1n
1o
nC11H23
nC7H15
OH
OH
OH
13
14
NBu3
NBu3
45
9
Trace
56
Table 1
Optimization of reaction conditionsa
nC5H11
1a
15
16
17
18
19
20
NBu3
11
74
70
52
62
4
3
11
Trace
76
N(nC6H17
N(nC6H13
NPr3
N(CH2Ph)3
3a
)
)
3
3
OH
NBu2
catalyst
1a
1a
1a
1a
NBu
(4-MePhCH2)2NBu
+
+
3
Trace
2a
3a
4a
1a
Catalyst
Entry
Ligand
Solvent
Yieldb (%)
a
Conditions: 1 (0.6 mmol), amine (0.2 mmol), RuCl3ꢀ3H2O (0.01 mmol), dppf
3a
4a
(0.01 mmol), PhCl (0.8 mL), 145 °C, 15 h under argon.
b
Isolated yields for the major products and GC yields for the minor products
1
2
3
4
5
6
7
8
RuCl3ꢀ3H2O
RuCl3ꢀ3H2O
RuCl3ꢀ3H2O
RuCl3ꢀ3H2O
RuCl3ꢀ3H2O
RuCl3ꢀ3H2O
RuCl3ꢀ3H2O
RuCl3ꢀ3H2O
None
dppp
dppb
PPh3
dppe
dppf
PCy3HBF4
BINAP
dppf
dppf
dppf
dppf
dppf
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
Xylene
DMF
DMSO
NMP
None
PhCl
PhCl
35
47
52
71
70
92
86
Trace
70
Trace
Trace
Trace
3
2
7
10
0
5
0
4
0
9
0
0
0
85
4
based on amines.
benzyl alcohols reacted smoothly with tribuylamine to give the
corresponding products in good yields (entries 4–6). Only a trace
amount of the product was observed when 4-nitrobenzyl alcohol
was used (entry 7). Ortho-substituted benzyl alcohols gave slightly
lower yields (entries 8 and 9). Similar result was obtained when 3-
methylbenzyl alcohol was used (entry 10). Good yields were
obtained when 1-naphthalenemethanol and 2-furanmethanol re-
acted with tributylamine (entries 11 and 12). To our delight, be-
sides benzyl alcohol and its derivatives, simple aliphatic alcohols
also turned out to be good substrates for this transformation. The
length of chain affected the selectivity significantly. When 1-
dodecanol was used as substrate, the mono-substituented product
was the major product (entry 13). However, 1-octanol and 1-hex-
anol reacted with tributylamine and gave the bis-substituented
amines as the major products in moderate yields (entries 14 and
15). Unfortunately, attempts to react secondary alcohols with ter-
tiary amines were unsuccessful.18
9
[Ru(p-cymene)Cl2]2
[RuCl2(COD)]n
Ru(acac)3
10
11
12
13
14
15
16
17
18c
19d
35
73
Ru(CO)(H)2(PPh3)3
RuCl3ꢀ3H2O
Trace
85
Trace
Trace
32
2
49
73
RuCl3ꢀ3H2O
dppf
dppf
dppf
dppf
dppf
RuCl3ꢀ3H2O
RuCl3ꢀ3H2O
RuCl3ꢀ3H2O
RuCl3ꢀ3H2O
RuCl3ꢀ3H2O
dppf
Trace
a
Conditions: 1a (0.6 mmol), 2a (0.2 mmol), catalyst (0.01 mmol), ligand
(0.01 mmol), solvent (0.8 mL), 145 °C, 15 h under argon.
b
GC yields based on tributyamine.
Reaction was carried out at 130 °C.
2 equiv of 1a was used.
c
d

2708
J. Luo et al. / Tetrahedron Letters 52 (2011) 2706–2709
Bu
References and notes
N
58%
C8H17
1. Lawrence, S. A. In: Amines Synthesis Properties and Applications; Cambridge
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Groups; John Wiley & Sons LTD: Chichester, 1996.
2. For selected reviews, see: (a) Salvatore, R. N.; Yoon, C. H.; Jung, K. W.
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Chem. Rev. 2008, 108, 3054; (f) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed.
2009, 48, 6954.
+
+
dppf
Bu
N
nC8H17NBu2
1a
+
16%
7%
chlorobenzene
145 oC, 15 h
Bu
N
Bu
Scheme 2. 4-Methylbenzyl alcohol reacts with dibutyloctylamine.
3. For reviews, see: Hartwig, J. F. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., Ed.; Wiley: New York, 2002; Jiang, L.; Buchwald,
S. L. In: Metal-Catalyzed Cross-Coupling Reactions, second ed; Wiley-VCH:
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Fischmeister, C.; Thomas, C.; Renaud, J. Chem. Soc. Rev. 2010, 39, 4130.
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Interscience: London, 1970. Chapter 2, pp 61-147.; For selected examples, see:
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Springer: New York, 2006; (b) Dobereiner, G.; Crabtree, R. Chem. Rev. 2010, 110,
681.
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Commun. 1981, 611; (b) Watanable, Y.; Tsuji, Y.; Ohsugi, Y. Tetrahedtron Lett.
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Yamaguchi, R. Org. Lett. 2010, 12, 1336.
Table 3
Amination of alcohol in chlorobenzene and in neata
NBu2
OH
cat
145 o
NBu
+
+
NBu3
C
R
R
2
R
1
2
3
4
Entry
R
Solvent
Yieldb (%)
3
4
1
2
3
4
CH3
CH3
F
Chlorobenzene
None
Chlorobenzene
None
84
2
87
2
9
75
10
81
F
a
Conditions:
1
(0.6 mmol), 2a (0.2 mmol), RuCl3ꢀ3H2O (0.01 mmol), dppf
(0.01 mmol), 145 °C, 15 h under argon.
b
Isolated yields for major products and GC yields for minor products.
8. (a) Tillack, A.; Hollmann, D.; Michalik, D.; Beller, M. Tetrahedron Lett. 2006, 47,
8881; (b) Hollmann, D.; Tillack, A.; Michalik, D.; Jackstell, R.; Beller, M. Chem.
Asian J. 2007, 2, 403.
Other tertiary amines were also investigated under the same
reaction conditions. 4-Methylbenzyl alcohol also reacted with
trioctylamine and trihexylamine and gave the corresponding
products in good yields (entries 16 and 17). However, tripropyl-
amine only gave moderate yield probably due to its low boiling
point (entry 18), which was further confirmed by using triethyl-
amine as substrate and less than 10% desired product was ob-
tained. Attempts to react alcohols with aromatic tertiary
amines and tribenzylamine (entry 19) were unsuccessful. Inter-
estingly, tertiary amine 3a can further react with 4-methylbenzyl
alcohol and gave the corresponding product in 76% yield (entry
20). Three products were observed when 1a reacted with dibuty-
loctylamine (Scheme 2).
Another feature of this kind of ruthenium-catalyzed direct
amination of alcohols with tertiary amines is that the mono-
and bis-substituted products can be synthesized selectively by
changing the solvent condition. For example, when p-methylben-
zyl alcohol and p-fluorobenzyl alcohol reacted with tributyl-
amine in chlorobenzene mono-substituted products were the
major products. In contrast, bis-substituted reaction was the ma-
jor reaction when the reaction was carried out in the absence of
solvent (Table 3).
9. (a) Saidi, O.; Blacker, A.; Farah, M.; Marsden, S.; Williams, J. M. J. Chem.
Commun. 2010, 46, 1541; (b) Hamid, M.; Liana Allen, C.; Lamb, G.; Maxwell, A.;
Maytum, H.; Watson, A.; Williams, J. M. J. J. Am. Chem. Soc. 2009, 131, 1766.
10. (a) Gunanathan, C.; Milstein, D. Angew. Chem., Int. Ed. 2008, 47, 8661; (b)
Yamaguchi, K.; He, J.; Oishi, T.; Mizuno, N. Chem. Eur. J. 2010, 16, 7199; (c)
Zweifel, T.; Naubron, J.; Grutzmacher, H. Angew. Chem., Int. Ed. 2009, 48, 559;
(d) Blank, B.; Michlik, S.; Kempe, R. Adv. Synth. Catal. 2009, 351, 2903; (e) Saidi,
O.; Blacker, A.; Farah, M.; Marsden, S.; Williams, J. M. J. Angew. Chem., Int. Ed.
2009, 48, 7375; (f) He, J.; Kim, J.; Yamaguchi, K.; Mizuno, N. Angew. Chem., Int.
Ed. 2009, 48, 9888; (g) Cui, X.; Shi, F.; Tse, M.; Gördes, D.; Thurow, K.; Beller, M.;
Deng, Y. Adv. Synth. Catal. 2009, 351, 2949; (h) Shi, F.; Tse, A.; Cui, X.; Gördes,
D.; Michalik, D.; Thurow, K.; Deng, Y.; Beller, M. Angew. Chem. Int., Ed. 2009, 48,
5912; (i) Shi, F.; Tse, M.; Zhou, S.; Pohl, M.; Radnik, J.; Hübner, S.; Jähnisch, K.;
Brücker, A.; Beller, M. J. Am. Chem. Soc. 2009, 131, 1775.
11. For imines formation from alcohols and amines, see: (a) Gnanaprakasam, B.;
Zhang, J.; Milstein, D. Angew. Chem., Int. Ed. 2010, 49, 1468; (b) Bähn, S.; Imm,
S.; Mevius, K.; Neubert, L.; Tillack, A.; Williams, J. M. J.; Beller, M. Chem. Eur. J.
2010, 16, 3590.
12. (a) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317, 790; (b)
Ghosh, S.; Muthaiah, S.; Zhang, Y.; Xu, X.; Hong, S. Adv. Synth. Catal. 2009, 351,
2643.
13. For reviews on C–N bonds formation using borrowing hydrogen, see: (a)
Guillena, G.; Ramón, D. J.; Yus, M. Angew. Chem., Int. Ed. 2007, 46, 2358; (b)
Hamid, M.; Slatford, P. A.; Williams, J. M. J. Adv. Synth. Catal. 2007, 349,
1555; (c) Lamb, G. W.; Williams, J. M. J. Chim. Oggi 2008, 26, 17; (d) Nixon,
T. D.; Whittlesey, M. K.; Williams, J. M. J. Dalton Trans. 2009, 753; (e)
Guillena, G.; Ramón, D. J.; Yus, M. Chem. Rev. 2010, 110, 1611; (f) Watson,
A.; Williams, J. M. J. Science 2010, 329, 635; (g) Fujita, K. I.; Yamaguchi, R.
Synlett 2005, 4, 560.
14. For other selected examples on C–N bonds formation using borrowing
hydrogen, see: (a) Watanable, Y.; Morisaki, Y.; Kondo, T.; Mitsudo, T. J. Org.
Chem. 1996, 61, 4214; (b) Cami-Kobeci, G.; Slatford, P.; Whittlesey, M. K.;
Williams, J. M. J. Bioorg. Med. Chem. Lett. 2005, 15, 535; (c) Hamid, M.;
Williams, J. M. J. Chem. Commun. 2007, 725; (d) Naskar, S.; Bhattacharjee, M.
Tetrahedron Lett. 2007, 48, 3367; (e) Hamid, M.; Williams, J. M. J. Tetrahedron
Lett. 2007, 48, 8263; (f) Blank, B.; Madalska, M.; Kempe, R. Adv. Synth. Catal.
2008, 350, 749; (g) Fujita, K. I.; Enoki, Y.; Yamaguchi, R. Tetrahedron 2008,
64, 1943; (h) Yamaguchi, R.; Kawagoe, S.; Asai, C.; Fujita, K. I. Org. Lett. 2008,
10, 181; (i) Lamb, G.; Watson, A.; Jolley, K.; Maxwell, A.; Williams, J. M. J.
Tetrahedron Lett. 2009, 50, 3374; (j) Shimizu, K.; Nishimura, M.; Satsuma, A.
ChemCatChem 2009, 1, 497; (k) Martínez, R.; Ramón, D.; Yus, M. Org. Biomol.
Chem. 2009, 7, 2176; (l) Bähn, A.; Tillack, A.; Imm, S.; Mevius, K.; Michalik,
D.; Hollmann, D.; Neubert, L.; Beller, M. ChemSusChem 2009, 2, 551; (m)
Fujita, K.; Komatsubara, A.; Yamaguchi, R. Tetrahedron 2009, 65, 3624; (n)
Pingen, D.; Muller, C.; Vogt, D. Angew. Chem., Int. Ed. 2010, 49, 8130; (o) Cui,
X.; Zhang, Y.; Shi, F.; Deng, Y. Chem. Eur. J. doi:10.1002/chem.201001915.;
In summary, we have developed a selective ruthenium-cata-
lyzed unsymmetric tertiary amine formation reaction using ter-
tiary amines and primary alcohols as starting materials. Ligand
and solvent both play a key role in this reaction. The reaction pro-
ceeded well for a range of different substrate. Further investigation
including the scope and mechanism is in progress in our
laboratory.
Acknowledgments
This work was supported by the National Natural Science Foun-
dation of China (20902076) and Xiangtan University ‘‘Academic
Leader Program’’ (09QDZ12). We thank Professor C.-J. Li (McGill
University) and Professor Q. H. Fan (ICCAS) for helpful discussions.

J. Luo et al. / Tetrahedron Letters 52 (2011) 2706–2709
2709
(p) Saidi, O.; Blacker, A.; Lamb, G.; Marsden, S.; Taylor, J.; Williams, J. M. J.
Org. Process Res. Dev. 2010, 14, 1046; (q) Cui, X.; Shi, F.; Zhang, Y.; Deng, Y.
Tetrahedron Lett. 2010, 51, 2048; (r) Martínez-Asencio, A.; Ramón, D. J.; Yus,
M. Tetrahedron Lett. 2010, 51, 325; (s) He, L.; Lou, X.; Ni, J.; Liu, Y.; Cao, Y.;
Fan, K. Chem. Eur. J. 2010, 16, 13965.
18. Typical experimental procedures: An oven-dried 10 mL reaction vessel was
charged with RuCl3ꢀ3H2O (2.6 mg, 0.01 mmol), dppf (5.6 mg, 0.01 mmol), 2
(0.6 mmol), and purged with argon three times.
1 (0.2 mmol) and
chlorobenzene (0.8 mL) were added to the sealed reaction vessel by
a
syringe. The resulting solution was stirred at 145 °C for 15 h. After cooling to
room temperature, the volatiles were removed under vacuum and the residue
was purified by column chromatography (silica gel, petroleum ether/ethyl
acetate) to give 3. All new compounds were characterized by means of 1H NMR,
13C NMR, MS (EI) and HR-MS. Compound 3a: 1H NMR (400 MHz, CDCl3, ppm) d
7.22 (d, J = 7.7 Hz, 2H), 7.12 (d, J = 7.7 Hz, 2H), 3.53 (s, 2H), 2.41 (t, J = 7.3 Hz,
4H), 2.35 (s, 3H), 1.46 (quintet, J = 7.3 Hz, 4H), 1.31 (sextet, J = 7.3 Hz, 4H), 0.90
(t, J = 7.3 Hz, 6H); 13C NMR (100 MHz, CDCl3, ppm) d 137.1, 136.0, 128.8, 128.7,
58.4, 53.6, 29.3, 21.1, 20.6, 14.0; MS (EI) m/z (%) 233, 190, 105 (100), 77; HR-MS
calcd for: C16H28N [M+H]+ 234.2216, found 234.2212.
15. There is one example of ruthenium-catalyzed reductive amination of
aldehydes with tertiary amines in moderate yields (the best yield is 54%) in
the presence of carbon monoxide (10 atm) at 180 °C; Cho, C. S.; Park, J. H.; Kim,
T. J.; Shim, S. C. Bull. Korean Chem. Soc. 2002, 23, 23.
16. For tertiary amines reacted with C–H bond, see: Guo, S. M.; Qian, B.; Xie, Y. J.;
Xia, C. G.; Huang, H. M. Org. Lett. 2011, 13, 522.
17. Feng, C.; Liu, Y.; Peng, S. M.; Shuai, Q.; Deng, G. J.; Li, C. J. Org. Lett. 2010, 12,
4888. A similar method is used for imine formation: Alessandro, Z.; Mata, J. A.;
Peris, E. Chem. Eur. J. 2010, 16, 10502.