Efficient and chemoselective alkylation of amines/amino acids using alcohols as alkylating reagents under mild conditions

Article abstract of DOI:10.1039/c0cc01487g

We report a mild and environmentally benign method for the synthesis of tertiary amines using alcohols as the alkylating reagents. Not only secondary amines such as piperazines but also amino acids and amino alcohols can be N-alkylated selectively. For N,O-benzyl protected amino alcohols, both N,O-de-benzylation and N-methylation were achieved in one-pot. The Royal Society of Chemistry.

Full text of DOI:10.1039/c0cc01487g

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Efficient and chemoselective alkylation of amines/amino acids using
alcohols as alkylating reagents under mild conditionsw
Chu-Pei Xu,a Zhen-Hua Xiao,a Bi-Qin Zhuo,a Yu-Huang Wanga and Pei-Qiang Huang*ab
Received 19th May 2010, Accepted 19th July 2010
DOI: 10.1039/c0cc01487g
We report a mild and environmentally benign method for the
synthesis of tertiary amines using alcohols as the alkylating
reagents. Not only secondary amines such as piperazines but
also amino acids and amino alcohols can be N-alkylated
selectively. For N,O-benzyl protected amino alcohols, both
N,O-de-benzylation and N-methylation were achieved in one-pot.
In connection with our interest in the development of simple
and efficient methodology,17 we report herein a mild and
efficient Pd/C-catalyzed alkylation of amines/amino acids
using alcohols as alkylating reagents.
In view of the broad spectrum of pharmacological activities
possessed by piperazine-containing molecules,18 and Pd/C
or Pd(OH)2/C as easily available heterogeneous catalysts,
piperazine derivative 1 was selected as the substrate, and the
former as catalysts for our investigations. The N-alkylations of
piperazines using different alcohols as the solvent, were
investigated with either 10%Pd/C or 20%Pd(OH)2/C as
catalyst at room temperature. The results are summarized
in Table 1. As can be seen from the Table, MeOH, EtOH,
n-PrOH and i-PrOH can serve as the alkylating agents; both
10%Pd/C and 20%Pd(OH)2/C can be used as the catalyst with
the former being more effective. It might be due to the steric
effect that the alkylation with i-PrOH required a longer time
and the reaction was incomplete.
Amines are an important class of compounds in both
chemistry and medicinal chemistry.1 Many N-methyl and
N,N-dimethyl amino acid residues are found in bioactive
natural products (vide infra).2 The classical methods for the
synthesis of amines, such as alkylation of amines with organo-
halides3 and reductive alkylation of amines with carbonyl
compounds,4,5 disobey to the principles of green chemistry,6,7
because in both methods, the starting materials, alkyl halides
and carbonyl compounds, need to be prepared from alcohols.
In addition, both their preparation and transformation to
amines involve environmentally hazardous reagents.
A survey of the literature revealed that Pd/C-catalyzed
alkylation of amines with alcohols can occur without the use
of hydrogen. However, the reactions need to be performed at
80–120 1C.19 Our controlled experiments showed that at room
temperature H2 was necessary for the N-alkylation of an
amine with an alcohol. A plausible mechanism is shown in
the ESIw, which involves firstly the conversion of an alcohol
into the corresponding aldehyde or ketone by Pd/C-catalyzed
dehydration, followed by the consecutive imine formation and
Pd/C-catalyzed hydrogenation to give the corresponding
amine.12b,20
The development of environmentally benign methods6
featuring amongst others, atom-economy,8 step-economy,9
and the use of readily available reagents and chemicals7 is
highly desirable, yet challenging. In this context, direct
conversion of C–H bonds10 or C–OH bonds11 has attracted
considerable attention. Transition metal-catalyzed amine
alkylation with alcohols has attracted much interest in recent
years.11,12 However, these methods are still subject to drawbacks
such as the use of inaccessible and expensive homogeneous
catalysts (e.g. Ru, Rh, Ir, etc.), restriction to aniline or
benzylic/allylic alcohols, or require harsh conditions.13,14 Very
recently, Isobe and co-workers reported a Pd/C catalyzed
one-pot reductive mono-alkylation of nitro aryls with
hydrogen.15a Pinto and co-workers observed an unexpected
one-pot azide reduction-N-dimethylation in methanol
(or diethylation in ethanol) in the presence of Pd/C and under
a hydrogen atmosphere at 70 psi.15b More recently, Ruano
and co-workers reported the RANEYs-nickel-catalyzed
mono-alkylation of primary amines and N-sulfinyl derivatives
with alcohols at room temperature.16 Nitriles have also been
used as alkylating agents for N-alkylation.15c,d
A shortcoming of the method is that the alcohol needs to be
used as a solvent. To overcome this drawback, the recovery
Table 1 Alkylation of amine 1 with alcoholsa
Entry Amine Alcohol (R3OH) T1/T2/hb Product (R) Y1/Y2 (%)b
a Department of Chemistry and Key Laboratory for Chemical Biology
of Fujian Province, College of Chemistry & Chemical Engineering,
Xiamen University, Xiamen, Fujian 361005, China.
E-mail: org500@xmu.edu.cn; Tel: +86-592-2180992
b The State Key Laboratory of Elemento-Organic Chemistry,
Nankai University, Tianjin 300071, China.
1
2
3
4
1
1
1
1
MeOH
EtOH
n-PrOH
i-PrOH
21/47
20/44
30/50
2a (Me)
2b (Et)
2c (n-Pr)
85/62
89/74
76/92
64/NDc
138/NDc 2d (i-Pr)
a
Reaction conditions: 0.1 mmol of amine in 5 mL of alcohol in the
presence of 100 mg of 10%Pd/C or 80 mg of 20%Pd(OH)2/C at
E-mail: pqhuang@xmu.edu.cn; Fax: +86-592-2186400;
Tel: +86-592-2182240
b
rt. T1, Y1 and T2, Y2 correspond to the reaction time and
w Electronic supplementary information (ESI) available: Experimental
procedures, 1H and 13C NMR spectra of new compounds, and a
plausible mechanism. See DOI: 10.1039/c0cc01487g
isolated yield using Pd/C or Pd(OH)2/C as the catalyst, respectively.
c
ND = not determined.
c
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Table 2 Alkylation of amino alcohol/amino acids with alcohols
under catalytic hydrogenation conditionsa
Alcohol
Entry Starting material (R3OH) T1/T2/hb Product
Y1/Y2
(%)b
1
2
MeOH 24/60
89/83
MeOH 48/NDc
87/ND
Fig. 1 Some N-methyl, and N,N-dimethyl-amino acid residues found
in bioactive natural products.
3
MeOH 27/59
90/94
and re-use of both the solvent and catalyst were investigated.
The results showed that the catalyst can be easily recovered by
a simple filtration and reused without a loss of activity after
four cycles (cf. ESIw). Similarly, about 80% of the solvent
(alcohol) can be recovered by distillation and recycled.
4
5
MeOH 76/ND
MeOH 72/ND
94/ND
92/ND
Encouraged by these results, we then proceeded to investigate
the applicability of this method for the direct synthesis of
N-methyl and N,N-dimethylamino acids.2 N,N-Dimethylamino
acids constitute a salient structural feature of cyclopeptide
alkaloids, a class of bioactive natural products with more than
200 members.2c,d For example, N,N-dimethyl valine (Dov, 3,
Fig. 1) is found in dolastatin 10 and dolastatin 15, as well as
their analogues TZT-1027 (auristatin PE), cemadotin
(LU103793), and synthadotin (ILX651), which are in clinical
trials as anticancer agents.21a,b This residue also exists in
grassystatins A–C, which are potent cathepsin E inhibitors
recently isolated from marine cyanobacteria;21c other N,N-
dimethylamino acid residues such as 4–6 are found in
cyclopeptide alkaloids.2c,d,22 In addition, N-methyl-trans-4-
hydroxy-L-proline (7) is a natural product;23 N-methylpipecolic
acid (Mep, 8) is found in tubulysins, a family of nine natural
products that are able to suppress the growth of cancer cells
with inhibitory activity exceeding that of the anticancer drugs
vinblastine, and Taxol, by 20- to 100-fold!24
6
7
MeOH 80/ND
93/ND
MeOH 88/ND
MeOH 29/ND
91/ND
72/ND
8
9
EtOH
EtOH
26/44
30/79
85/75
86/96
As can be seen from Table 2, with 10%Pd/C or
20%Pd(OH)2/C as a catalyst, the methylation of both primary
and secondary amino acids in methanol went smoothly and
produced the corresponding N-methyl or N,N-dimethylamino
acids in good to excellent yields (Table 2, entries 1–8).
10
a
Reaction conditions: 0.1 mmol of amine in 5 mL of alcohol in the
presence of 100 mg of 10%Pd/C or 80 mg of 20%Pd(OH)2/C
Remarkably, N-methylation of amino alcohol and phenol
acids can be achieved in excellent chemoselectivity to afford
exclusively the N-methylated product in high yields (entries 2
and 8). Similarly, reactions in ethanol gave the corresponding
N-ethylamino acids in good to excellent yields (entries 9–10).
In this manner, natural products 3 to 6 were synthesized
directly from the corresponding amino acid in high yield.
Next, we carried out the one-pot debenzylation-N-methylation
of polyhydroxylated pyrrolidine derivative 21. To our satisfaction,
under the 10%Pd/C-catalyzed hydrogenolysis conditions in
methanol, the reaction of compound 21 gave, in one-pot, the
desired debenzylation-N-methylation product N-methyl-2,5-
dideoxy-2,5-imino-D-mannitol (N-methyl-DMDP) 2225 in
89% yield (Scheme 1). DMDP26,27 is a strong inhibitor of
b
at rt. T1, Y1 and T2, Y2 correspond to the reaction time and
isolated yield using Pd/C or Pd(OH)2/C as the catalyst, respectively.
c
ND = not determined.
a- and b-glucosidases but shows weak inhibition against
a-fucosidase.26
Interestingly, subjecting N,O-dibenzylbulgecinine 23 to
20%Pd(OH)2/C or 10%Pd/C catalysts in methanol at room
temperature, produced N-methylbulgecinine27 24 in almost
quantitative yield (Scheme 2).
In summary, we have developed a mild (at rt, 1 atm H2)
heterogeneous Pd/C or Pd(OH)2/C-catalyzed method for the
monoalkylation of secondary amines and amino acids using
c
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Scheme 1 One-pot debenzylation-N-methylation of pyrrolidine 21.
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Scheme
2 One-pot O-debenzylation-N-transalkylation of N,O-
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alcohols as alkylating agents. Using this method, naturally
occurring amino acid residues 3 to 8 have been synthesized
directly from the corresponding amino acid in high yields.
Another feature of this method is the high efficiency in the
one-pot debenzylation-N-methylation of polyhydroxylated
pyrrolidine derivative 21, and in the one-pot O-debenzylation-
N-transalkylation of N-benzylamine 23. Given that the benzyl
group is the most widely used protecting group for amines and
alcohols, and the N-methylated tertiary amine motif is present
in many bioactive alkaloids and drugs, our method would find
applications in the efficient synthesis of such amines.
The authors are grateful to the NSF of China (20832005),
and the National Basic Research Program (973 Program) of
China (Grant No. 2010CB833200) for financial support.
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This journal is The Royal Society of Chemistry 2010