N-Alkylation of phenethylamine and tryptamine

Article abstract of DOI:10.1016/j.bmcl.2004.11.050

A clean and efficient method for the N-alkylation of tryptamine and phenethylamine, employing alcohols as the alkylating agents, has been developed. The reaction proceeds via catalytic electronic activation, involving an iridium catalyst which activates the alcohol by borrowing hydrogen from the substrate, returning it later in the catalytic cycle. Some examples of N-heterocyclisation have been performed employing a diol as the substrate.

Full text of DOI:10.1016/j.bmcl.2004.11.050

Bioorganic & Medicinal Chemistry Letters 15 (2005) 535–537
N-Alkylation of phenethylamine and tryptamine
Gerta Cami-Kobeci, Paul A. Slatford, Michael K. Whittlesey and Jonathan M. J. Williams*
Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
Received 28 October 2004; revised 17 November 2004; accepted 18 November 2004
Available online 24 December 2004
Abstract—A clean and efficient method for the N-alkylation of tryptamine and phenethylamine, employing alcohols as the alkyl-
ating agents, has been developed. The reaction proceeds via catalytic electronic activation, involving an iridium catalyst which
activates the alcohol by borrowing hydrogen from the substrate, returning it later in the catalytic cycle. Some examples
of N-heterocyclisation have been performed employing a diol as the substrate.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The ability to prepare a large number of synthetically
useful and pharmacologically active compounds, either
by traditional or high throughput methods, is becoming
increasingly important. Herein we report an efficient,
atom economic, one-pot method for the N-alkylation
of tryptamine and phenethylamine, giving water as the
only by-product.
NMe2
H
N
OH
Me
S
HN
O
O
N
H
OH
Sumatriptan
Nylidrin
Figure 1.
The tryptamine sub-structure is present in numerous
naturally occurring and synthetic compounds, many of
which exhibit important pharmacological activity. For
example, a number of 5-alkyltryptamine derivatives
(collectively known as ÔtriptansÕ, e.g., sumatriptan)1 are
used as antimigraine drugs, binding to the 5-HT1D, 5-
HT1B and 5-HT1F receptors with high affinities.2 Some
N,N-disubstituted tryptamines have been reported to
show psychotomimetic activity, although there is evi-
dence to suggest that the tryptamine derivatives are
metabolised in vivo to more active forms.3 Bis(phen-
ylalkyl)amines have been tested following reports that
nylidrin, a nonpiperidine analogue of ifenprodil, was a
potent NR2B-selective N-methyl-D-aspartate receptor
antagonist (potentially useful as neuroprotectants,
anti-convulsants, analgesics and agents that augment
the effects of L-DOPA for the treatment of ParkinsonÕs
disease) (Fig. 1).4
mercially available iminophosphorane 3.5 The reaction
proceeds via a strategy of Ôborrowing hydrogenÕ, which
we have previously exploited in other procedures such
as the conversion of alcohols to longer chain alkanes.6
As shown in Scheme 1, hydrogen is temporarily re-
moved from the alcohol 1 to afford an intermediate
aldehyde 4, which undergoes an aza-Wittig reaction
with the iminophosphorane 3 to afford the imine 5.
The hydrogen is then returned by the catalyst,
reducing the imine 5 to an amine 2.
R
R
OH
R
NHPh
1
2
M
As part of our continued interest into catalytic electronic
activation, we recently reported a method for the con-
version of alcohols 1 into phenylamines 2 using the com-
MH2
R
O
NPh
Ph3P NPh
4
3
5
Keywords: Iridium; Tryptamine; Oxidation; Reduction.
*
Scheme 1. Borrowing hydrogen in the synthesis of amines via an aza-
Wittig reaction.
Corresponding author. Tel.: +44 1225 383942; fax: +44 1225
386231; e-mail: chsjmjw@bath.ac.uk
0960-894X/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.11.050

536
G. Cami-Kobeci et al. / Bioorg. Med. Chem. Lett. 15 (2005) 535–537
Whilst this strategy was used successfully for the prepa-
ration of b-aminoarenes, it proved to be difficult to re-
move the triphenylphosphine oxide that was formed
during the reaction. Imines are readily formed by the
reaction of an aldehyde or ketone with an amine, and
are traditionally driven to completion by the azeotropic
removal of water. We therefore turned our attention to
the use of free amines, which we hoped would form imi-
nes in situ with only the formation of water as a by-
product. Preliminary results indicated that this reaction
was possible, and indeed the removal of water with the
use of molecular sieves enabled these reactions to
achieve higher yields. The N-alkylation of amines with
alcohols has been reported previously with ruthenium
catalysts, though more forcing conditions were
required.7
The N-alkylated tryptamine derivatives 13 and 14 could
also be prepared by the reaction of tryptophol 15 with
amines. Indeed, using this approach with benzylamine
11 allowed us to prepare N-benzyltryptamine 13 in
92% isolated yield with no trace of the intermediate
imine (Scheme 4).
Whilst we had observed no formation of tertiary amines
in any of the preceding reactions, we reasoned that the
use of diols with primary amines would lead to the form-
ation of N-heterocycles. Indeed, there is precedent for
this reaction under forcing conditions,9 and during the
preparation of this manuscript Fujita et al. reported
the N-heterocyclisation of primary amines with diols
using a Cp*Ir catalyst.10 As shown in Scheme 5, a diol
16 could undergo dehydrogenation to provide a mono-
aldehyde 17, which undergoes reductive amination to
19. The aminoalcohol 19 is then oxidised to generate
the aminoaldehyde 20 which cyclises in situ to the enam-
ine 21 (or iminium salt), which in turn is reduced to the
heterocycle 22. During the catalytic cycle, there is no net
oxidation or reduction, but the temporary removal of
hydrogen is required in order for the reaction to
proceed.
N-Benzylphenethylamine 6 was prepared by two related
routes, as shown in Scheme 2. The iridium catalysed
reaction of benzyl alcohol 7 with phenethylamine 8 pro-
vided the expected product (65%) as well as a quantity of
the nonreduced imine 9 (35%). An alternative synthesis
employing phenethyl alcohol 10 with benzylamine 11
also afforded the desired product 6, though in this case
without any trace of the corresponding imine, in 93%
isolated yield.8
As previously mentioned, our particular interests were
in the preparation of N-alkylated tryptamine derivatives
(vide supra). The reaction of tryptamine 12 with benzyl
alcohol 7 and with phenethyl alcohol 10 proceeded with-
out any over-alkylation. However, the reaction employ-
ing benzyl alcohol resulted in a lower yield, presumably
as a consequence of the formation of a small amount of
imine that had not been reduced (Scheme 3).
OH
N
H
H
N
Ph
(i)
15
n
N
H
H2N
Ph
n
n = 1, 13, 92% isolated yield
n = 2, 14, 91% isolated yield
n = 1, 11
n = 2, 8
Isolated Yield
Scheme 4. Reagents and conditions: (i) 5 mol % [Ir(COD)Cl]2,
˚
5 mol % dppf, 3 A molecular sieves, PhMe, 24 h.
(i)
Ph
Ph
Ph
6
65%
Ph
OH
H2N
Ph
Ph
N
H
7
8
9
35%
N
- H2O
N
(i)
O
NHR
NHR
NR
R
Ph
Ph
Ph
NH2
93%
HO
Ph
N
H
20
19
21
10
11
6
MH2
M
Scheme 2. Reagents and conditions: (i) 5 mol % [Ir(COD)Cl]2,
˚
5 mol % dppf, 3 A molecular sieves, PhMe, reflux, 24 h.
N
R
22
OH
OH
OH
OH
OH
NH2
16
17
H
N
N
H
M
Ph
n
(i)
12
N
H
MH2
HO
Ph
n = 1, 13, 64% isolated yield
n = 2, 14, 86% isolated yield
n
H2NR
O
n = 1,7
n = 2,10
18
Scheme 3. Reagents and conditions: (i) 5 mol % [Ir(COD)Cl]2,
˚
5 mol % dppf, 3 A molecular sieves, PhMe, 24 h.
Scheme 5. A proposed mechanism for the conversion of diols to cyclic
amines.

G. Cami-Kobeci et al. / Bioorg. Med. Chem. Lett. 15 (2005) 535–537
537
4. Tamiz, A. P.; Whittemore, E. R.; Zhou, Z.-L.; Huang,
J.-C.; Drewe, J. A.; Chen, J.-C.; Cai, S. X.; Weber, E.;
Woodward, R. M.; Keana, J. F. W. J. Med. Chem. 1998,
41, 3499, and references cited therein.
5. Cami-Kobeci, G.; Williams, J. M. J. Chem. Commun.
2004, 1072.
6. (a) Edwards, M. G.; Jazzar, R. F. R.; Paine, B. M.;
Shermer, D. J.; Whittlesey, M. K.; Williams, J. M. J.;
Edney, D. D. Chem. Commun. 2004, 90; (b) Edwards, M.
G.; Williams, J. M. J. Angew. Chem., Int. Ed. 2002, 41,
4740.
NH2
N
H
12
N
n
(i)
N
H
n
OH
OH
n = 1, 25, 83% isolated yield
n = 2, 26, 72% isolated yield
n = 3, 27, 40% isolated yield
n = 1, 16
n = 2, 23
n = 3, 24
7. Watanabe, Y.; Tsuji, Y.; Ige, H.; Ohsugi, Y.; Ohta, T.
J. Org. Chem. 1984, 49, 3359.
8. The procedure for the preparation of 6 is typical: To a
nitrogen purged pressure tube containing [IrCl(COD)]2
(16 mg, 0.02 mmol), dppf (27 mg, 0.05 mmol), K2CO3
(6 mg, 0.05 mmol) and benzyl amine (109 lL, 1.00 mmol),
was added phenethyl alcohol (120 lL, 1.00 mmol), fol-
lowed by anhydrous toluene (1 mL). The tube was sealed
and then heated at 110 ꢁC for 24 h. After cooling to room
temperature the reaction was quenched with wet diethyl
ether (10 mL) and poured into water (50 mL) and diethyl
ether (50 mL). The ether layer was separated and remain-
ing aqueous layer further extracted with diethyl ether
(3 · 50 mL). The combined organic extracts were washed
with saturated brine (50 mL), dried (MgSO4), filtered and
concentrated in vacuo. Purification by flash column
chromatography on silica using petroleum ether (bp 40–
60 ꢁC)/dichloromethane/ethyl acetate (2:1:1) as the eluent
afforded N-benzyl-2-phenethylamine 6 as a pale yellow
Scheme 6. Reagents and conditions: (i) 5 mol % [Ir(COD)Cl]2,
˚
5 mol % dppf, 3 A molecular sieves, PhMe, 24 h.
We were pleased to find that reaction of tryptamine (12)
with the appropriate diol (16, 23 and 24) resulted in
good conversion to the corresponding pyrrolidine 25,
and piperidine 26, and in reasonable isolated yield into
azepane 27 (Scheme 6).
In conclusion, a simple strategy for N-alkylation of
amines has been developed and applied to the prepara-
tion of tryptamine derivatives. The work has also been
extended to provide a simple procedure for the elabora-
tion of tryptamine into heterocyclic derivatives.
We would like to thank the British Council Macedonia
(G.C.K.) and the EPSRC (P.A.S.) for financial support.
1
liquid (0.232 g, 100% conversion, 93% isolated yield): H
NMR (300 MHz, CDCl3, 25 ꢁC): d = 2.17 (br s, 1H, NH),
2.79 (m, 4H, 2 · CH2), 3.73 (s, 2H, CH2), 7.09–7.26 (m,
10H, CHAr); 13C NMR (75.4 MHz, CDCl3, 25 ꢁC):
d = 36.8, 51.0, 54.3, 126.5, 127.3, 128.5, 128.8, 128.9,
129.18, 140.5, 140.7; IR (liquid film): mmax (cmÀ1) 3313
(NH), 3060 (CAr–H), 2922 (N–CH2), 2846 (C–H), 1718
(CAr–CAr), 1454 (CAr–CAr), 1354 (CAr–CAr); MS (EI+,
References and notes
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Å
70 eV): m/z (%) 211 (16), [MÅ+], 120 (65) [(MÀ(C8H9 ))+],
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3. Brimblecombe, R. W.; Downing, D. F.; Green, D. M.;
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3525.