One-pot solvent-free reductive amination with a solid ammonium carbamate salt from CO2 and amine

Article abstract of DOI:10.1039/c4ra07558g

Many amines are liquid and their handling is inconvenient compared with the corresponding solids. We transformed a liquid (S)-(-)-1-phenylethylamine 1 to the corresponding neutral solid form 2 by reacting with carbon dioxide. We performed reductive aminat

Full text of DOI:10.1039/c4ra07558g

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
One-pot solvent-free reductive amination with a
solid ammonium carbamate salt from CO2 and
amine†
Cite this: RSC Adv., 2014, 4, 46203
a
b
a
Philjun Kang, Kyu Myung Lee, Won Koo Lee, Kyu Hyung Lee,a Byeongno Lee,a
Received 24th July 2014
Accepted 15th September 2014
*
c
a
*
Jaeheung Cho and Nam Hwi Hur
DOI: 10.1039/c4ra07558g
www.rsc.org/advances
Many amines are liquid and their handling is inconvenient compared derivatives5 or carbon monoxide.6 Therefore, it is convenient to
with the corresponding solids. We transformed a liquid (S)-(ꢀ)-1- convert liquid amines to the corresponding neutral solids,
phenylethylamine 1 to the corresponding neutral solid form 2 by which are expected to show the same reactivity as parent amine.
reacting with carbon dioxide. We performed reductive amination of 2
with various aldehydes 3 under solvent-free conditions to provide native for the synthesis of carbamates.7 Although Aresta et al.
Carbon dioxide (CO2) has been efficiently used as an alter-
secondary amines 5 in high yields.
reported the synthesis of carbamate salts with carbon dioxide,8
most researchers have used CO2 for the synthesis of carbamate
esters by reacting the amine, CO2 and an electrophile such as
alkyl halide, epoxide or terminal alkynes with transition metal
catalysts.9 Recently, Peeters et al. employed CO2 as a temporary
amine protecting group as well.10
In this report we demonstrate the direct use of neutral
ammonium carbamate salts in solvent-free reductive amination
reactions. The reductive amination reaction is useful for the
synthesis of medicinally relevant enzyme inhibitors,11 dendritic
polyglycerols,12 and highly functionalized amine derivatives.13
Hence, the reductive amination reaction remains one of the
most powerful and widely utilized transformation that allows
the direct conversion of carbonyl compounds into amines using
simple operations.14 We employed previously reported
methods15,16 to prepare a stable neutral solidied ammonium
Environmental issues are of growing concern and scientists are
trying to eliminate extra steps in reactions and also avoid extra
reagents including unwanted by-products. In typical organic
reactions, large amounts of organic solvents are used univer-
sally. Even if they are recycled with suitable treatment, they
contribute to environmental and energy-related problems.
Many efforts have been made to design environmentally benign
processes to eliminate or reduce hazardous substances during
organic syntheses.1 Among those, solvent-free condition is a
very attractive from both environmental and economic points of
view. Very recently, we reported some advantages of solvent-free
reactions in terms of selectivity as well as reaction rates.2
Amine is a ubiquitous functional group, whose derivatives
are versatile building blocks for the synthesis of natural prod-
ucts, pharmaceuticals, and ne chemicals.3 Since liquid free
amines are inconvenient to handle and also prone to oxidation,
it is common to convert liquid amines to the corresponding
acid salts. However, this necessitates a neutralization step with
a base when we need to use free amines. Alternately, the car-
bamic acid forms of amines have been generated by reaction
with toxic or cumbersome reagents including phosgene4 and its
Scheme
phenylethylamine with CO2.
1
Solid ammonium carbamate formation of (S)-(ꢀ)-1-
aDepartment of Chemistry, Sogang University, Seoul 121-742, Korea. E-mail: wonkoo@
sogang.ac.kr; nhhur@sogang.ac.kr
bKRICT, Daejeon 305-600, Korea
cDepartment of Emerging Materials Science, DGIST, Daegu 711-873, Korea
† Electronic supplementary information (ESI) available: Experimental procedures,
compound characterization data (1H and 13C NMR spectra, TGA, IR spectra, XRD
data for compounds 2 as well as 1H NMR and 13C NMR spectra for 4a, and 5a–5r).
CCDC 953131. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c4ra07558g
Scheme 2 Solvent-free imine formation.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 46203–46207 | 46203

View Article Online
RSC Advances
Communication
absence of solvent.16a We recently found that the solid amine
formation could be successfully performed with dry ice (solid
CO2) at 1 atm and 50 mmol scale reductive amination also
proceeded without any difficulties.16b,c We carried out the cata-
lytic hydrogenation of the imines with Adams' catalyst (PtO2)
under 1 atm of H2 without solvents. Here, we report a highly
effective, convenient and environmentally benign process for
the preparation of secondary amines via one-pot solvent-free
reductive amination of aldehydes.
We prepared a stable solid (S)-(ꢀ)-1-phenylethylamine carba-
mate ammonium salt 2 by reacting liquid (S)-(ꢀ)-1-phenylethyl-
amine 1 with CO2 to produce a white solid (Scheme 1) and this salt
is stable enough to store at room temperature in air.2
Fig. 1 ORTEP plot of (S,E)-N,N-dimethyl-4-((1-phenylethyl-imino)
methyl)aniline 4a, at 30% probability level of the thermal ellipsoids.
Hydrogen atoms are not labeled for clarity.
We proposed the structure of the salt 2 based on the
following observations: 1 equiv. of 2 reacted with 2 equiv. of an
aldehyde to give the corresponding imine as the sole product.
Additionally, we characterized 2 by elemental analysis, 1H NMR,
13C NMR, thermal gravimetric analysis (TGA), IR spectroscopy,
and X-ray powder diffraction (XRD) (ESI Fig. S1–S4†). TGA data
for 2 show that 2 completely disappears above 105 ꢁC (ESI
Fig. S3†), indicating that 2 is sublimed below that temperature.
Scheme 3 One-pot solvent-free reductive amination of aldehydes.
ꢁ
Interestingly, the boiling point of 1 is 187 C, which is much
higher than the sublimation temperature of the solid congener
2. The sublimation of 2 is presumably due to the easy dissoci-
ation of CO2 in 2. Decarboxylation of 2 liberates free amine,
carbamate salt of (S)-(ꢀ)-1-phenylethylamine by reacting liquid
(S)-(ꢀ)-1-phenyl-ethylamine with CO2. Then we applied the solid
amine equivalent to form imines using various aldehydes in the
Table 1 One-pot solvent-free reductive amination via catalytic hydrogenation with various catalystsa
Entry
1
Aldehyde 3
Product 5
Reducing agentb
Timec (h)
Yieldd (%)
PtO2
Pt/C
Pd/C
NaBH4
16
12
6
90
85
49
87
4-(Dimethylamino)-benzaldehyde 3a
0.5
PtO2
Pt/C
Pd/C
NaBH4
14
20
14
0.5
97
89
98
91
2
3
3-Fluoro-benzaldehyde 3b
3-Chloro-benzaldehyde 3c
PtO2
PtO2
PtO2
Pt/C
Pd/C
NaBH4
14
26
7
20
36
0.5
95
91
94
92
48
88
e
f
g
PtO2
20
20
20
0.5
96
38
5
Pt/Cg
Pd/Cg
NaBH4
4
3-Thiophene-carboxaldehyde 3d
91
a
Method A: solvent-free catalytic hydrogenation, Method B: stoichiometric reduction with NaBH4 in MeOH. b Metal catalyst (1.8 mol%), NaBH4 (1.1
equiv.), MeOH (1.5 M, 0.67 mL) at 25 ꢁC. c Reaction time for hydrogenation or reduction of imine. d Isolated yield. e 0.60 mol%. f 2.9 mol%. g At 40 ꢁC.
46204 | RSC Adv., 2014, 4, 46203–46207
This journal is © The Royal Society of Chemistry 2014

View Article Online
Communication
RSC Advances
which is less likely to experience close interaction among aldehyde without stirring, 2 is converted to the reactive free
themselves, unlike neat liquid amine. This supports remarkably amine, which readily reacts with an aldehyde to yield the cor-
high reactivity of 2 towards aldehydes even in the solid state. responding imine.
Upon heating the mixture (>60 ꢁC) of solidied amine 2 and
Table 2 One-pot reductive amination with diverse aldehydes using PtO2 and NaBH4
Entry
1
Aldehyde 3
Product 5
Timea (h)
10/0.5
Yieldb (%)
98d/93e
Benzaldehyde 3ec
2
3
4-Anisaldehyde 3fc
13/0.5
13/0.5
97d/96e
95d/87e
3-Methoxy-benzaldehyde 3gc
4
5
6
7
1-Naphthaldehyde 3hc
26/0.5
26/0.5
8/0.5
95d/95e
96d/96e
97d/90e
93d/88e
2-Methoxy-1-naphthaldehyde 3if
4-tert-Butyl-benzaldehyde 3jc
1-Methylpyrrole-2-carboxaldehyde 3kc
15/0.5
8
1-Methylindole-3-carbaldehyde 3lf,g
2-Furaldehyde 3mc
43/0.5
30/0.5
35/0.5
3/0.5
96d/84e
95d/96e
93d/94e
96d/93e
98d/92e
9
10
11
12
3-Furaldehyde 3nc
Trimethylacetaldehyde 3oc
Isobutyraldehyde 3pc
3/0.5
13
Cyclohexanecarbox-aldehyde 3qc
Cyclopentanecarbox-aldehyde 3rc
3/0.5
3/0.5
92d/88e
93d/84e
14
a
b
c
d
Reaction time for catalytic hydrogenation/NaBH4 reduction of imine. Isolated yield. Imine synthesis: 60 ꢁC, 30 min. Yield of catalytic
e
f
hydrogenation using PtO2 (1.8 mol%). Yield of reduction with NaBH4 (1.1 equiv.) and MeOH (1.5 M, 0.67 mL). Imine synthesis: 100 ꢁC, 1 h.
g
Trace amount of MeOH (20–30 mL) was added for mixing of the corresponding imine and PtO2 catalyst.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 46203–46207 | 46205

View Article Online
RSC Advances
Communication
Solvent-free imine formation was achieved by combining the Furthermore, it seems that the amount of PtO2 is related to
solidied amine 2 and aldehydes 3 with 1 : 2 molar ratio and reaction time: when 2.9 mol% of PtO2 was used, reaction was
warming the mixture to 60 or 100 ꢁC under air without stirring completed in 7 h, giving 94% yield; otherwise using 0.60 mol%
(Scheme 2). We observed water formation within 20 min, which of PtO2 took 26 h with 91% yield (Table 1, entry 3).
was the sign of the conversion of the aldehyde to the corre-
We extended this solvent-free PtO2 reduction system to other
sponding imine 4 by dehydration. We did the comparison aldehydes since PtO2 provides better results in reducing func-
experiments with a 1 : 1 mixture of neat (S)-1-phenylethylamine tionalized imines. Reaction time is not affected by placement of
and aldehydes to obtain the corresponding imine with some –OMe substituents on aromatic rings (Table 2, entries 2 and 3).
side products. The reason for the clean reaction with the solid The fused ring system, naphthyl, signicantly retards the cata-
amine equivalent is the presence of a small amount of the lytic hydrogenation (Table 2, entries 4 and 5) while alkyl
amine in the reaction mixture from the gradual decarboxylation substitution on the phenyl ring speeds catalytic hydrogenation
of the ammonium salt upon heating the mixture. As a repre- (Table 2, entry 6). In case of the heteroaromatic rings such as
sentative example of the imine formation reactions, 2 equiv. of pyrrole, indole, and furan give a much slower reaction rate
4-(dimethylamino)benzaldehyde 3a was reacted with 1 equiv. (Table 2, entries 7–10). On the other hand, aliphatic imines are
of 2, to produce (S,E)-N,N-dimethyl-4-((1-phenylethylimino)- converted to secondary amines within short reaction time
methyl)aniline 4a almost quantitatively without any side (Table 2, entries 11–14).
product.‡
We demonstrated that a solidied amine 2, prepared from
We conrmed the structure of the imine 4a using a single the reaction of a liquid amine with CO2, could be used as a
crystal X-ray diffraction (see ESI Table S1–S3†). Single crystals for stable precursor for the reductive amination process. The
the diffraction study were grown from a methylene chloride– overall reaction proceeded in one-pot and solvent-free condition
hexane (1 : 4) solution. Fig. 1 shows the ORTEP diagram of 4a, and we successfully tested the reaction with a variety of alde-
which is based on the amine and aldehyde units linked by an hydes. This reaction system is convenient and environmentally
imine (–N]C–) group, and the conguration of 1 (S) has not been benign to be a general method for reductive amination with a
changed during the formation of this imine via compound 2.
wide range of aldehydes.23
ꢀ
The bond distance of N1–C9 in the imine group is 1.266 A
which is similar to those of typical N]C double bonds.17,18 The
bond angles of C7–N1–C9 and N1–C9–C10 are 117.00ꢁ and
123.50ꢁ, respectively (see Table S2 and S3,† ESI). Detailed data
are presented in Table S3 (see ESI†).
Acknowledgements
WKL acknowledges the nancial support (2012M3A7B4049646
and 2013R1A1A2005524) funded by the Ministry of Education,
Science, and Technology through the National Research Foun-
dation of Korea. This work was supported by the Korea CCS R&D
Center (KCRC) grant funded by the Korea government (Ministry
of Science, ICT & Future Planning) (2013M1A8A1035853). BL
thanks the Basic Science Research Program through the
National Research Foundation of Korea (NRF) funded by the
Ministry of Education (2012R1A12043256). KHL thanks the
Research Institute for Basic Science in Sogang University.
Aer obtaining the imine 4 from the reaction of 1 equiv. of
solidied amine 2 with 2 equiv. of aldehyde 3, a catalytic
amount of PtO2, Pt/C, or Pd/C was added with an atmospheric
pressure of H2. The one-pot catalytic hydrogenation proceeded
in the absence of solvent to produce the secondary amine in
high yields.19 For comparison, the reduction of the imine with
1.1 equiv. of NaBH4 was conducted in the presence of MeOH
(1.5 M, 0.67 mL) (Scheme 3) and those results were summarized
in Table 1. Table 1 shows that PtO2 is better than Pt/C and Pd/C
in terms of reaction time and chemical yield. The entire reac-
tion proceeded in the absence of solvent, which resulted in
secondary amines smoothly even in the case of solid imines
(Table 1, entry 1). Although reduction with NaBH4 was
completed within 0.5 h, it was performed in MeOH to mix the
imine and NaBH4, which led to extra purication step. When we
used 4-(dimethylamino)-benzaldehyde 3a and Pd/C, we
obtained 49% yield of the desired product 5a with 41% of
the debenzylation product, 4-(aminomethyl)-N,N-dimethyl-
aniline.20 On the other hand, using PtO2 and Pt/C catalysts
under the same conditions provided much higher yield without
forming the over reduction product (Table 1 entry 1). In addi-
tion, Pd/C is not appropriate in the reaction with halogen
substituted aromatic aldehyde due to the hydrogenolysis of the
halogen (Table 1, entry 3).21 For imines containing sulfur,
catalytic hydrogenation proceeded with 5% conversion using
Pd/C and 38% with Pt/C. The low conversions are mainly due to
the poisoning of Pd and Pt surfaces by sulfur. However, the PtO2
catalyst provided high yield as anticipated (Table 1, entry 4).22
Notes and references
‡ X-ray crystallographic data for (S,E)-N,N-dimethyl-4-(((1-phenylethyl)imino)
methyl)aniline 4a: C17H20N2, monoclinic, P2(1), Z ¼ 2, a ¼ 8.5299(3), b ¼
3
ꢀ1
ꢁ
˚
˚
6.0689(2), c ¼ 13.7293(5) A, b ¼ 91.554(2) , V ¼ 710.46(4) A , m ¼ 0.070 mm
,
rcalcd ¼ 1.180 g cmꢀ3, R1 ¼ 0.0353, and wR2 ¼ 0.0930 for 3410 unique reections
and 175 variables.
1 (a) Y. Monguchi, Y. Fujita, S. Hashimoto, M. Ina,
T. Takahashi, R. Ito, K. Nozaki, T. Maegawa and H. Sajiki,
Tetrahedron, 2011, 67, 8628; (b) P. T. Anastas and
J. C. Warner, Green Chemistry: Theory and Practice, Oxford
´
University, Oxford, 1998; (c) J. Bonnamour, T.-X. Metro,
J. Martinez and F. Lamaty, Green Chem., 2013, 15, 1116; (d)
M. Li, X.-L. Lv, L.-R. Wen and Z.-Q. Hu, Org. Lett., 2013, 15,
1262.
2 B. Lee, P. Kang, K. H. Lee, J. Cho, W. Nam, W. K. Lee and
N. H. Hur, Tetrahedron Lett., 2013, 54, 1384.
3 (a) E. M. Brzostowska and A. Greer, J. Am. Chem. Soc., 2003,
125, 396; (b) T. Doi, M. Yoshida, K. Shin-ya and
46206 | RSC Adv., 2014, 4, 46203–46207
This journal is © The Royal Society of Chemistry 2014

View Article Online
Communication
RSC Advances
T. Takahashi, Org. Lett., 2006, 8, 4165; (c) X. Feng, S. Chen, 15 (a) B. Lee, S. H. Kang, D. Kang, K. H. Lee, J. Cho, W. Nam,
Y. Xu, W. Du, Q. Luo and B.-F. Liu, J. Sep. Sci., 2008, 31, 824.
4 D. P. N. Satchell and R. S. Satchell, Chem. Soc. Rev., 1975, 4,
231.
O. H. Han and N. H. Hur, Chem. Commun., 2011, 47,
11219; (b) B. Lee, K. H. Lee, J. Cho, W. Nam, O. H. Han
and N. H. Hur, Org. Lett., 2011, 13, 6386.
5 S. Raucher and D. S. Jones, Synth. Commun., 1985, 15, 1025. 16 (a) B. Lee, K. H. Lee, B. Y. Lim, J. Cho, W. Nam and N. H. Hur,
6 (a) T. W. Leung and B. D. Dombek, J. Chem. Soc., Chem.
Commun., 1992, 205; (b) T. Mizuno, J. Takahashi and
A. Ogawa, Tetrahedron, 2002, 58, 7805.
7 (a) D. Chaturvedi and S. Ray, Monatsh. Chem., 2006, 137, 127;
(b) E. Quaranta and M. Aresta, Carbon Dioxide as Chemical
Adv. Synth. Catal., 2013, 355, 389; (b) Preparation of 2 in
multi gram scale. A glass vial was charged with 6.1 g (50
mmol) of (S)-1-phenylethanamine 1 and dry ice (20 g).
Aer 1 hour, the liquid (S)-1-phenylethanamine 1 was
transformed to a white solid powder of 2 quantitatively.
The weight change from 1 to 2 was 1.1 g which means CO2
(25 mmol) reacted with 1 in 2 : 1 ratio; (c) 4-Anisaldehyde
(4.76 g, 4.30 mL, 2.00 mmol) was placed in a round-
bottomed ask and the solidied amine 2 (5.00 g, 1.00
mmol ) was added. The ask was warmed to 60 ꢁC for 6
hours and the condensed water vapor was wiped then
allowed to cool to room temperature. To the ask was
added PtO2 (198 mg, 5 mol%) and the hydrogenation
proceeded at room temperature under 1 atm of H2 for 15
hours to provide 95% of the reductive amination product
with no side product.
Feedstock, Wiley-VCH Verlag GmbH
&
Co. KGaA,
Weinheim, 2010, and references cited therein.
8 (a) M. Aresta and E. Quaranta, Tetrahedron, 1992, 48, 1515;
(b) M. Aresta, D. Ballivet-Tkatchenko, D. B. Dell'Amico,
M. C. Bonnet, D. Boschi, F. Calderazzo, R. Faure, L. Labella
and F. Marchetti, Chem. Commun., 2000, 1099.
9 (a) Y. Yoshida, S. Ishii and T. Yamashita, Chem. Lett., 1984,
1571; (b) Y. Yoshida, S. Ishii, M. Watanabe and
T. Yamashita, Bull. Chem. Soc. Jpn., 1989, 62, 1534; (c)
Y. Yoshida and S. Inoue, Chem. Lett., 1978, 139; (d)
Y. Yoshida and S. Inoue, Bull. Chem. Soc. Jpn., 1978, 51,
559; (e) Y. Yoshida and S. Inoue, J. Chem. Soc., Perkin 17 (a) N. Arai, N. Utsumi, Y. Matsumoto, K. Murata, K. Tsutsumi
Trans. 1, 1979, 3146; (f) F. Kojima, T. Aida and S. Inoue, J.
Am. Chem. Soc., 1986, 108, 391; (g) W. D. McGhee,
D. P. Riley, M. E. Christ and K. M. Christ, Organometallics,
1993, 12, 1429; (h) M. Aresta and E. Quaranta, Chem.Tech.,
1997, 27, 32; (i) P. G. Jessop, T. Ikariya and R. Noyori,
Chem. Rev., 1995, 95, 259.
and T. Ohkuma, Adv. Synth. Catal., 2012, 354, 2089; (b)
J. Waser, B. Gaspar, H. Nambu and E. M. Carreira, J. Am.
Chem. Soc., 2006, 128, 11693; (c) J. F. Larrow,
E. N. Jacobsen, Y. Gao, Y. Hong, X. Nie and C. M. Zepp, J.
Org. Chem., 1994, 59, 1939; (d) H. N. Khatri, U.S. Pat.,
4997945, 1991.
10 A. Peeters, R. Ameloot and D. E. De Vos, Green Chem., 2013, 18 H.-K. Fun, H. Kargar and R. Kia, Acta Crystallogr., Sect. E:
15, 1550. Struct. Rep. Online, 2008, 64, o1894.
11 J. Samanen, T. Cash, D. Narindray, E. Brandeis, W. Adams Jr, 19 (a) B. T. Cho and S. K. Kang, Tetrahedron, 2005, 61, 5725; (b)
H. Weideman, T. Yellin and D. Regoli, J. Med. Chem., 1991,
34, 3036.
B. T. Cho and S. K. Kang, Synlett, 2004, 9, 1484.
20 S. Ram and L. D. Spicer, Synth. Commun., 1987, 17, 415.
´
´
´
12 F. Koç, M. Wyszogrodzka, P. Eilbracht and R. Haag, J. Org. 21 (a) M. A. Aramendıa, V. Borau, I. M. Garcıa, C. Jimenez,
Chem., 2005, 70, 2021. A. Marinas, J. M. Marinas and F. J. C. Urbano, R. Acad. Sci.
¨
´
13 (a) V. I. Tararov, R. Kadyrov, T. H. Riermeier and A. Borner,
Chem. Commun., 2000, 1867; (b) R. Apodaca and W. Xiao,
Org. Lett., 2001, 3, 1745; (c) B. Basu, S. Jha,
Paris, Serie IIc., 2000, 3, 465; (b) F. J. Urbano and
J. M. Marinas, J. Mol. Catal. A: Chem., 2001, 173, 329; (c)
B. Sreedhar and V. S. Rawat, Synth. Commun., 2012, 42, 2490.
Md. M. H. Bhuiyan and P. Das, Synlett, 2003, 555; (d) 22 (a) P. Albers, J. Pietsch and S. F. Parker, J. Mol. Catal. A:
T. Gross, A. M. Seayad, M. Ahmad and M. Beller, Org. Lett.,
2002, 4, 2055; (e) K. Miura, K. Ootsuka, S. Suda,
Chem., 2001, 173, 275; (b) J. K. Dunleavy, Platinum Met.
Rev., 2006, 50, 110.
H. Nishikori and A. Hosomi, Synlett, 2001, 1617; (f) 23 We also prepared many ammonium carbamate salts from
I. Shibata, T. Suwa, E. Sugiyama and A. Baba, Synlett, 1998,
1081.
14 B. Sreedhar, P. S. Reddy and D. K. Devi, J. Org. Chem., 2009,
74, 8806.
various alkyl primary amines successfully. However, we
could not prepare stable salts from secondary amines and
aromatic amine.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 46203–46207 | 46207