Diastereoselective pictet-spengler reactions of a tethered 2-aminoimidazole

Article abstract of DOI:10.1071/CH13346

The diastereoselective Pictet-Spengler reaction of aminopropyl-2- aminoimidazole with enantiopure aldehydes has been investigated. With amino acid-derived aldehydes, anti stereochemistry is favoured, with a diastereoselectivity up to 92% achievable. The absolute stereochemistry of the products was determined through synthesis of a rigid derivative and from NMR data in combination with molecular modelling. The diastereoselectivity was shown to be dependent on the steric bulk of the amino acid side chain and independent of the nitrogen protecting group. Lewis acids catalysed the reaction but did not affect the diastereoselectivity.

Full text of DOI:10.1071/CH13346

CSIRO PUBLISHING
Aust. J. Chem. 2014, 67, 184–191
Full Paper
http://dx.doi.org/10.1071/CH13346
Diastereoselective Pictet Spengler Reactions
]
of a Tethered 2-Aminoimidazole
A
A B
,
Sudhir R. Shengule and Peter Karuso
A
Department of Chemistry and Biomolecular Sciences, Macquarie University,
Sydney, NSW 2109, Australia.
B
Corresponding author. Email: peter.karuso@mq.edu.au
The diastereoselective Pictet–Spengler reaction of aminopropyl-2-aminoimidazole with enantiopure aldehydes has been
investigated. With amino acid-derived aldehydes, anti stereochemistry is favoured, with a diastereoselectivity up to 92 %
achievable. The absolute stereochemistry of the products was determined through synthesis of a rigid derivative and from
NMR data in combination with molecular modelling. The diastereoselectivity was shown to be dependent on the steric
bulk of the amino acid side chain and independent of the nitrogen protecting group. Lewis acids catalysed the reaction but
did not affect the diastereoselectivity.
Manuscript received: 3 July 2013.
Manuscript accepted: 28 September 2013.
Published online: 8 November 2013.
Introduction
has not previously been reported. For tryptamines and phenyl-
ethylamines, amino acid aldehydes have been successfully
employed for the synthesis of a number of biologically impor-
tant natural products and been the subject of detailed stereo-
chemical investigations.[13] We reasoned that a stereospecific
version of the Pictet–Spengler reaction with imidazoles could
provide access to new chiral imidazole alkaloids and be useful in
The Pictet–Spengler reaction was first discovered in 1911 by
Ame´ Pictet and Theodor Spengler (Fig. 1),[1] and has been
found useful for the synthesis of tetrahydo-b-carbolines and
tetrahydroisoquinolines and recently been proposed to be a
common biosynthetic reaction for the construction of a range of
alkaloids.[2]
The reaction has been used to great avail in classic syntheses
such as haemultine,[3] manzamine alkaloids,[4] yohimbinoid
alkaloids,[5] and ecteinascidin 743.[6]
Although the Pictet–Spengler reaction has been widely
studied in indole and benzene chemistry,[7] less is known about
the Pictet–Spengler cyclisation of other heterocycles such as
imidazoles, an important component of many marine natural
products.[8] In 1948, Folkers et al. reported the first example of a
Pictet–Spengler reaction between histidine and vitamin B6 to
form a tetrahydroimidazopyridine (1) (Fig. 2).[9]
Me
MeO
OMe
NH
ϩ
NH
NH2
Fig. 1. Pictet–Spengler reaction between phenylethylamine and acetalde-
hyde dimethyl acetal involving an intermediate iminium ion.
N
Since then, there have been sporadic reports on Pictet–
Spengler reactions between various aldehydes and ketones and
histamine, histidine or histinol.[10] Notably, these reactions are
generally reported as base-catalysed, probably going through a
mechanism like that shown in Fig. 3. However, it is possible that
base is simply required to avoid the non-nucleophilic imidazo-
lium ion.
CHO
HO
OH
NH
COOH
HO
H2N
N
OH
N
ϩ
HOOC
N
H
N
N
H
1
We used this reaction to good effect in the concise total
synthesis of ageladine A (3) and in a range of analogues starting
from 2-aminohistamine (2) and 4,5-dibromopyrrole carboxyal-
dehyde or other aryl aldehydes (Fig. 4).[11]
Subsequently, Horne and coworkers used this method with a
variety of aliphatic and aromatic aldehydes in the synthesis of
imidazoazepine (azulene) analogues (5) of ageladine A from
2-aminohomohistamine (4), the basic building block for all the
oroidin alkaloids (Fig. 5).[12]
Fig. 2. Pictet–Spengler reaction of histidine with vitamin B6.
R
R
N
N
N
RCHO
N
HN
N
H
H2N
N
H
N
H
BH
Unlike indole- and phenyl-ethylamine, the enantioselective
or diastereoselective Pictet–Spengler reaction of imidazoles
Fig. 3. Proposed base-catalysed mechanism for the Pictet–Spengler reac-
tions of imidazole.
Journal compilation Ó CSIRO 2014
www.publish.csiro.au/journals/ajc

Diastereoselective Pictet–Spengler Reactions
185
Br
Br
Br
(entry 8) groups had little effect on the diastereomeric ratio,
suggesting that the protecting group on nitrogen is sufficiently
distant from the reaction centre not to influence the geometry of
the transition state (TS).
NBoc
CHO
H2N
N
Br
BocN
N
NH2
N
H
Sc(OTf)3, EtOH
rt, 5h, 44 %
NH
H2N
Most Pictet–Spengler reactions are acid-catalysed, with
imidazoles being somewhat unusual in being base-catalysed
(Fig. 3).[13] We were interested to know if a Lewis acid could
improve the diastereoselectivity through complexation of the
TS. We previously observed that the combination of Lewis acid
and Brønsted base increased the rate of Pictet–Spengler cyclisa-
tion in the six-membered ring system.[11] Unfortunately, scan-
dium, indium, and lanthanum did not significantly change the
diastereomeric ratio (Table 2) but did increase the rate of the
reaction (entries 3–5), with scandium triflate showing margin-
ally better activity than the other two. Temperature can have a
dramatic effect on stereoselectivity by favouring the kinetic
product and temperature-dependent changes in the diastereos-
electivity of the standard Pictet–Spengler reaction of tryptamine
with enantiopure aldehydes is known.[18] When we screened
reactions at lower temperatures (entries 1 and 2), a small
improvement in the diastereomeric ratio was obtained at 08C
but no reaction was observed at ꢀ788C. The reaction was also
found to proceed without any catalyst (entry 6), albeit at a slower
rate. Base catalysis is evident by comparing entry 1 (Table 1)
and entry 6 (Table 2). In the former, the reaction proceeded in
72 % yield in 3–4 h in the presence of triethylamine. The free
base, without base catalysis, reacted in a lower yield (67 %) in
8 h but the diastereoselectivity was largely unaffected.
2
N
H
chloranil,
80ЊC
CHCI3,
8h, 65 %
Br
HN
N
Br
N
H2N
N
H
3
Fig. 4. Concise synthesis of ageladine A using Pictet–Spengler reaction.
R
RCHO
Na2CO3
NH
NH
N
NH2
H2N
H2N
N
H2O/EtOH
1 day, 23ЊC
N
H
.2HCI
4
Br2, MeSO3H
110ЊC, 16h
R
The coupling constant obtained for H10a–H10 for all the
major isomers 7 is between 8 and 9 Hz and for minor isomers 8 is
between 5 and 6 Hz in [D4]MeOH. This information suggested
that all the major and minor products had the same stereoche-
mistry. However, the observed coupling constants and nuclear
Overhauser effects (NOEs) could not definitely be used to assign
the C10a–C10 dihedral.
N
N
H2N
N
5
Fig. 5. Synthesis of imidazoazepine analogues of ageladine A using
Pictet–Spengler reaction.
To assign the stereochemistry, we prepared rigid tricyclic
compounds 10 and 12 by reacting 9 and 11 (derived from
D-alaninal) with carbonyldiimidazole in moderate yields
(Scheme 1). Poor yields were obtained for the imidazolidinone
when the reaction was carried out in the recommended solvent
(acetonitrile)[19] but DMF was found suitable. Initial attempts
using triphosgene or thiophosgene in dichloromethane (DCM)
gave complex mixtures.
the stereospecific synthesis of imidazole-containing natural
products such as mikimopine, cucumopine, and analogues.[14]
As a first step in this direction, we decided to investigate the
potential for diastereoselectivity of the base-catalysed Pictet–
Spengler reaction between 2-aminoimidazoles and enantiopure
aldehydes (6) derived from amino acids.
Result and Discussion
The structure of the tricyclic product was confirmed by
heteronuclear multiple bond correlation (HMBC) spectroscopy
As a starting point, we decided to extend the chemistry devel-
oped by Horne using 2-aminohomohistamine (4), which was
synthesised in three steps from ornithine.[15] A series of amino
acid aldehydes (6) were synthesised from the corresponding
amino acids using the method of Kanellis,[16] except after
reduction of the protected amino acid with BH3-THF, the
intermediate alcohols were oxidised using the Dess–Martin
reagent.[17] Screening solvents (water, aqueous ethanol, etha-
nol) and bases (Na2CO3, K2CO3, triethylamine), we were
pleased to see a good yield of the Pictet–Spengler product using
triethyamine in alcohol at room temperature (rt). Thus, stirring
4 with Boc-L-alaninal (6a) gave the corresponding bicyclic
product with a moderate diastereomeric excess (de) of 56 %
(7a/8a, Table 1), favouring anti stereochemistry over syn.
Similar results were obtained with other amino acid-derived
aldehydes (entries 2–6). The de increased from phenylalaninal
(72 %) to leucinal (84 %) and valinal (92 %), suggesting that
steric factors play an important role. Changing the protecting
group from Boc to the less bulky Cbz (entry 7) or ethylcarbamate
3
where (H6)2, H10, H10a, and the amide NH showed JCH
correlations to the urea carbonyl (C8) at 159.5 ppm (Scheme 1,
3
Fig. S1 in the Supplementary Material). Other important JCH
correlations, including NH, H6a, and H10 to the C10a, and NH
and H10a to C10 could also be seen in the 2D NMR (Fig. S1).
Unfortunately, the NMR coupling constants between H10a
and H10 (Fig. S2 in the Supplementary Material) were again
very similar (6.1 and 7.1 Hz), which did not allow differentiation
based on a calculated dihedral using the well-known Karplus
relationship.[20] Molecular modelling (simulated annealing) of
the tricyclic ureas (10 and 12) generated 100 random structures,
each minimised to only three possible dihedrals (Fig. S3 in
the Supplementary Material). For the (10R*,10aS*)-isomer
(10), there are three minima for the C10b–C10 dihedral at
,142–1448. For the (10R*,10aR*)-isomer (12), similarly
three minima are seen but the dihedral ranges from ꢀ12 to
ꢀ208. The calculated coupling constants (6.8, 7.4 Hz)[20] were
not different enough to positively determine the absolute

186
S. R. Shengule and P. Karuso
Table 1. Pictet Spengler reaction of 4 and amino acid derived aldehydes 6
]
R1HN
R1HN
H
R
R
H
R
NH
N
NH
N
R1HN
CHO
H2N
6
H2N
4
N
H
N
H
TEA, EtOH
rt, 3–4
h
7
8
Entry
Aldehyde
Major isomer (anti)
Minor isomer (syn)
YieldA [%]
RatioB (drC) anti : syn (7 : 8)
BocHN
BocHN
H
H
N
CHO
NH
NH
NH
N
(S)
1
6a
6b
7a
7b
8a
72
78 : 22
78 : 22
H2N
H2N
NHBoc
N
H
N
H
BocHN
BocHN
H
N
H
N
CHO
NH
(R)
2
3
4
5
8b
79
85
62
71
H2N
H2N
NHBoc
N
H
N
H
Ph
Ph
BocHN
H
BocHN
H
N
CHO
(S)
NH
NH
N
Ph
6c
6d
6e
7c
7d
7e
8c
8d
8e
86 : 14
96 : 4
96 : 4
H2N
H2N
H2N
NHBoc
H2N
N
H
N
H
BocHN
BocHN
CHO
H
N
H
N
(S)
NH
NH
NH
NHBoc
H2N
N
H
N
H
BocHN
BocHN
CHO
H
N
H
N
(R)
NH
NHBoc
H2N
N
H
N
H
BocHN
BocHN
CHO
(S)
H
N
H
N
NH
NH
NHBoc
6
6f
7f
8f
89
92 : 8
H2N
H2N
N
H
N
H
CbzHN
CbzHN
H
N
H
N
CHO
NH
NH
NH
NH
(S)
7
8
6g
6h
7g
7h
8g
8h
65
90
72 : 28
74 : 26
H2N
H2N
NHCbz
N
H
N
H
EtOOCHN
EtOOCHN
H
N
H
N
CHO
(R)
H2N
H2N
NHCOOEt
N
H
N
H
AYield for 7 and 8.
BRatios calculated using 1H NMR spectrum of the diastereomeric mixture.
CDiastereomeric ratio.
stereochemistry but suggested that the major isomer was 10 and
that the minor was 12.
However, the modelling results indicated that the distance
between the C10–Me and H10a were quite different. For the
differentiated through the NOE. Thus 1D-rotation frame
Overhauser effect (ROE) experiments on compounds 10 and
12 (Fig. S4 in the Supplementary Material), under identical
conditions, resulted in enhancement of all neighbouring protons
(Fig. 6). Both compounds showed a 0.9 ꢁ 0.05 % ROE from
C10–Me to H10, confirming that the ROE experiments were
˚
(10R*, 10aR*) isomer, the distance was ,3.5 A and for the other
˚
isomer, it was ,2.8 A. These differences should be easily

Diastereoselective Pictet–Spengler Reactions
187
Table 2. Lewis acid catalysed Pictet Spengler reaction of 4 (free base)
]
and Boc-L-alaninal
NH
HN
H
H
H
H
NH
R
HN
HN
NH2
H2N
N
N
HN
R
BocHN
BocHN
PG
PG
H
H
BocHN
CHO
NH
NH
N
N
6a
H
N
H
N
4
H2N
H2N
EtOH
(free base)
N
H
N
H
H2N
NH2
H
H
N
N
N
N
R
7a
8a
R
HN
HN
PG
(S∗,S∗)-
PG
(R∗,S∗)-
Entry
Catalyst
Temperature
Time
YieldA
[%]
Anti : synB
(20 mol-%)
[8C]
[h]
7a : 8a
Fig. 7. Putative transition states for the Pictet–Spengler reaction favouring
the anti TS (PG: protecting group).
1
2
3
4
5
6
Sc(OTf)3
ꢀ78
0
8
6
1
2
1
8
0
55
82
75
79
67
–
81 : 19
77 : 23
77 : 23
74 : 16
75 : 25
rt
In(OTf)3
La(OTf)3
rt
Felkin–Anh transition state model, where ‘R’ is the large
substituent, the (S*,S*) TS should be favoured. As the protecting
group (PG) is remote, it should not affect the TS as observed
experimentally (Table 1; entries 2, 7, and 8).
rt
rt
AYield for 7 plus 8.
BDiastereoisomeric ratios calculated using 1H NMR spectroscopy.
Conclusions
H
H
N
H2N
H
For the first time, the diastereoselective version of the Pictet–
Spengler reaction of aminopropyl-2-aminoimidazole has been
investigated with enantiopure amino acid-derived aldehydes.
The reaction proceeded with good to excellent diastereoselec-
tivity, depending only on the steric bulk of the amino acid side
chain. Different protecting groups on nitrogen and various
Lewis acids did not change the diastereoselectivity but Lewis
acids did accelerate the reaction even in the presence of excess
base. Based on detailed NMR experiments and molecular
modelling, it was eventually possible to assign anti stereo-
chemistry to the major isomer and syn to the minor isomer.
TFA/DCM
1:1
O
O
H
CDI
N
NH
N
N
7b
8b
40ЊC
2h, 85 %
H2N
H2N
100ЊC
DMF, 53 %
N
H
N
H
9
10
H
H
H
N
H2N
H
TFA/DCM
1:1
N
CDI
NH
N
N
40ЊC
2h, 85 %
H2N
H2N
100ЊC
DMF, 53 %
N
H
N
H
11
12
Experimental
Scheme 1. Synthesis of imidazolinones 10 and 12; arrows indicate 3JCH
correlation observed in the HMBC.
General Methods
Chloroform, dichloromethane, ethanol, and methanol were
obtained from Froline Australia and were fractionally distilled
before use from anhydrous potassium carbonate. Merck silica
gel 60 (230–400 mesh) was used for flash column chromatog-
raphy. All the reagents were obtained from commercial sources
and used without further purification. NMR spectra were
recorded in 5-mm Pyrex NMR tubes (Wilmald, USA; 507-PP)
on Bruker DPX400 or DRX600 NMR spectrometers, operating
at 400 and 600 MHz respectively for protons. Chemical
shifts were referenced to the solvent peaks: dH 3.31 and dC 49.1
for CD3OD, dH 7.25 and dC 77.01 for CDCl3, and dH 2.49 and
dC 39.5 for [D6]DMSO.
0.13
0.25
0.85
H
0.95
H H
H
H3C
H3C
N
N
N
10
O
0.13
Ha
O
0.94
N
0.08
N
10a
0.07
Ha
N
H
H
H2N
H2N
Hb
N
H
N
H
Hb
12
10
(10aR, 10R)
(10aS, 10R)
Fig. 6. NOE correlation for major (left) and minor (right) isomers prepared
from D-alanine.
All two-dimensional (2D) spectra were recorded with quad-
rature detection in both dimensions using time proportional
phase incrimination (TPPI). For double-quantum filtered
correlation spectroscopy (DQF-COSY) and rotating frame
Overhauser effect spectroscopy (ROESY)[21] experiments,
2048 data points were collected in t2 and 512 in t1, and between
24 and 80 transients were collected at each increment. Rela-
xation delays and solvent suppression were as for the 1D
spectra. Gradient-selective 1D-ROESY difference spectra were
recorded with a continuous-wave pulse equivalent to a 4-kHz
spinlock of 250-ms duration using selective refocussing with
a Gaussian-shaped pulse.[22] ROE enhancements were mea-
sured as a percentage of the irradiated peak and not compen-
sated for offset from the carrier frequency. Carbon–hydrogen
nearly identical. Of particular note was that the major isomer
had a 0.94 % enhancement of H10a but for the corresponding
minor isomer, the enhancement was 10ꢂ smaller, showing that
in the major isomer (10), the methyl group and H10a are on the
same side of the ring (10R, 10aS). The 1D-ROE measurements
confirmed the molecular modelling results, indicating that the
(10R, 10aS)-isomer is the major isomer formed in the Pictet–
Spengler reaction of L-alaninal.
The selection for this diastereomer can be rationalised by
looking at the putative TS in the Pictet–Spengler reaction. After
formation of the imine, base-catalysed nucleophilic attack of the
imidazole requires a TS like that shown in Fig. 7. Applying the

188
S. R. Shengule and P. Karuso
correlation (HSQC) was achieved via a sensitivity-enhanced
double INEPT transfer using echo/antiecho-TPPI gradient
(80 : 20.1) selection.[23] Two thousand and forty-eight data
points were collected in t2 (128 scans per increment) with a
1.3-s recycle delay with decoupling during acquisition. In t1, 512
increments were used (10–120 ppm) and the INEPT sequence
was optimised for an X–H coupling of 145 Hz. A gradient ratio
of 80 : 20.1 was used to select echo/antiecho-TPPI phase sensi-
tivity. HMBC spectra were obtained via zero and double
quantum coherence with a low-pass J-filter to suppress one-
bond couplings. No decoupling was used during the acquisi-
tion and the results were magnitude-calculated. A long-range
coupling of 20 Hz was used for HMBC selection. Data were
processed using the Bruker TopSpin (version 1.4) software. The
spectra were zero-filled twice in F1 and once in F2 and
processed with either squared sine-bell (p/2- or p/3-shifted)
or Lorentzian–Gaussian window functions. The spectra were
referenced and phased in both dimensions. A baseline correction
was subsequently applied in F2 and F1 if necessary.
Molecular dynamics and minimisation were performed using
the Insight II/Discover3 Molecular Modelling System. The
compound was built using the Builder module in InsightII,
and energy-minimised briefly. Molecular dynamics simulations
were performed at 1000 K for 0.1 ns and a structure sampled
every 10 ps in order to generate 100 random structures. Each
structure was cooled to 200 K over 8 ps using a simulated
annealing approach. This was followed by minimisation of each
structure, involving steepest descents, conjugate gradients, and
4-(3-Aminopropyl)-1H-imidazol-2-amine 4
To a stirred solution of 4-(3-aminopropyl)-1H-imidazol-
2-amine dihydrochloride 4 (500 mg, 2.35 mmol) in ethanol
(10 mL) was added triethylamine (0.65 mL, 4.71 mmol), the
solvent removed under reduced pressure and the dark-brown
residue subject to column chromatography over aluminium
oxide using a gradient of 10 : 90–35 : 65 (MeOH/DCM saturated
with ammonia) to aminopropylimidazole free base (310 mg,
94 %) as a thick yellow liquid.
General Procedure of Pictet–Spengler
Cyclisation of 4 (Dihydrochloride Salt)
To a stirred solution of 4 (0.0023 mol) in ethanol (5 mL) was
added triethylamine (0.0070 mol) and the reaction mixture
stirred at room temperature for 10 min, followed by addition of
the aldehyde 6 (0.0027 mol). The reaction mixture was stirred
for a further 3–6 h, after which the solvent was removed under
reduced pressure and the residue subjected to flash chroma-
tography (silica gel) using a gradient of 5 : 95–15 : 85 (MeOH/
DCM saturated with ammonia), collecting 7 and 8 as a mixture
(Table 1). Diastereomeric ratios were obtained from NMR
spectra and the diastereoisomers separated by more careful flash
chromatography (silica gel).
Lewis Acid-catalysed Pictet–Spengler
Cyclisation of 4 (Free Base)
To a stirred solution of 4 (free base, 0.0023 mol) in ethanol
(5 mL) was added aldehyde 6a (0.0027 mol) and Lewis acid
(20 mol-%) and the reaction mixture stirred at room temperature
for 1–8 h. The solvent was removed under reduced pressure and
the residue subjected to flash chromatography (silica gel) using
a gradient of 5 : 95–15 : 85 (MeOH/DCM saturated with
ammonia), yielding a mixture of 7a and 8a as a yellowish solid
(Table 2). Diastereomeric ratios were obtained from NMR
spectra and separated by flash chromatography (silica gel).
In the case of entries 1, 2, and 6 (Table 2), the reactions were
carried out on the free base without addition of catalyst or base.
quasi-Newton–Raphson minimisation until the final maximum
derivative was less than 0.0001 kcal molꢀ1 ꢀ1. The MMFF94
A
˚
force field was used in all Discover3 calculations.[24]
Preparation of 4-(3-Aminopropyl)-1H-imidazol-2-amine
4 dihydrochloride
Compound 4 was synthesised using a method of Horne et al.[15]
Ornithine hydrochloride (5 g, 0.029 mol) was dissolved in a dry
ethanol (50 mL) and the reaction mixture cooled to 08C. After
10 min, thionyl chloride (2.83 mL, 0.037 mol) was slowly added
to the reaction mixture, keeping the temperature below 58C. The
reaction mixture was then warmed to room temperature and then
refluxed for 8 h, after which solvent was removed under reduced
pressure yielding ornithine ethyl ester dihydrochloride (5.82 g,
89 %) as a white solid. dH (400 MHz, [D6]DMSO) 8.76 (bs, 3H),
8.27 (bs, 3H), 4.16 (m, 2H), 3.94 (t, J 6.6, 1H), 2.79–2.68 (m,
2H), 1.90–1.80 (m, 2H), 1.79–1.58 (m, 2H), 1.21 (t, J 7.4, 3H).
Ornithine ethyl ester dihydrochloride was dissolved in water
(50 mL) and the solution cooled to 08C. Sodium amalgam
(109.2 g, 0.22mol) was slowly added to the reaction mixture
over a period of 30 min. During the addition, the pH of the
reaction mixture was maintained at 1–3 using dropwise addition
of 15 % hydrochloric acid. When the pH remained constant and
the evolution of gas had ceased, the solution was decanted to
remove mercury. The pH of the solution was maintained at 4.5 by
addition of 1 M sodium hydroxide. The aldehyde so formed was
further heated to 958C with an aqueous solution of cyanamide
(9.6 mL, 0.114 mol) for 2 h. The solvent was removed, leaving
behind a thick yellow residue, which was triturated with meth-
anol. The filtrate was concentrated and recrystallised (ethanol) to
yield aminopropylimidazole dihydrochloride (1.92 g, 42 %) as
a yellow solid. dH (400 MHz, [D6]DMSO) 12.33 (s, 1H), 11.79
(s, 1H), 8.31 (bs, 2H), 7.37 (bs, 3H), 6.61 (s, 1H), 2.77–2.65
(m, 2H), 2.50 (t, J 6.7, 2H), 1.88–1.77 (m, 2H). Lit.[15a]
(10S,4R)-tert-Butyl-(10-(2-amino-1,4,5,6,7,8-
hexahydroimidazo[4,5-c]azepin-4-yl)ethyl)carbamate 7a
½aꢃ2D6 21.0 (c 0.053 in EtOH). dH (400 MHz, CD3OD) 3.89–4.00
(m, 1H), 3.49 (d, J 8.8, 1H), 3.07–3.18 (m, 1H), 2.85–2.95
(m, 1H), 2.47–2.70 (m, 2H), 1.62–1.86 (m, 2H), 1.43 (s, 9H),
1.06 (d, J 6.6, 3H).dC (100 MHz, CD3OD) 157.9, 148.0, 129.9,
127.5, 80.1, 60.7, 48.5, 46.1, 29.7, 28.8, 26.1, 19.3. m/z (high
resolution mass spectrometry, HRMS) 296.2078 [M þ H]þ;
C14H26N5O2 requires 296.2087.
(10S,4S)-tert-Butyl-(10-(2-amino-1,4,5,6,7,8-
hexahydroimidazo[4,5-c]azepin-4-yl)ethyl)carbamate 8a
26
½aꢃD ꢀ9.2 (c 0.003 in EtOH). dH (400 MHz, CD3OD) 4.04–4.13
(m, 1H), 3.57 (d, J 5.1, 1H), 3.10–3.20 (m, 1H), 2.83–2.92
(m, 1H), 2.61–2.72 (m, 1H), 2.47–2.57 (m, 1H), 1.71–1.89
(m, 2H), 1.39 (s, 9H), 1.12 (d, J 6.8, 3H). dC (100 MHz, CD3OD)
157.5, 148.3, 129.9, 128.2, 80.0, 61.0, 47.8, 30.0, 28.7, 25.7,
17.1. m/z (HRMS) 318.1900 [M þ Na]þ; C14H25N5O2Na
requires 318.1900.
(10R,4S)-tert-Butyl-(10-(2-amino-1,4,5,6,7,8-
hexahydroimidazo[4,5-c]azepin-4-yl)ethyl)carbamate 7b
26
½aꢃD ꢀ21.7 (c 0.028 in EtOH). dH (400 MHz, CD3OD) 3.90–
4.00 (m, 1H), 3.50 (d, J 8.8, 1H), 3.07–3.18 (m, 1H), 2.85–2.95

Diastereoselective Pictet–Spengler Reactions
189
(m, 1H), 2.48–2.69 (m, 2H), 1.63–1.86 (m, 2H), 1.43 (s, 9H),
1.06 (d, J 6.5, 3H). dC (100 MHz, CD3OD) 157.8, 148.0, 130.0,
127.5, 80.1, 60.7, 48.5, 46.2, 29.7, 28.8, 26.1, 19.3. m/z (HRMS)
318.1906 [M þ Na]þ; C14H25N5O2Na requires 318.1900.
(10S,4R)-Benzyl-(10-(2-amino-1,4,5,6,7,8-
hexahydroimidazo[4,5-c]azepin-4-yl)ethyl)carbamate 7g
½aꢃ2D6 21.9 (c 0.067 in EtOH). dH (400 MHz, CD3OD) 7.38–7.21
(m, 5H), 5.07 (s, 2H), 4.09–3.98 (m, 1H), 3.54 (d, J 8.8, 1H),
3.17–3.05 (m, 1H), 2.92–2.79 (m, 1H), 2.70–2.46 (m, 2H),
1.90–1.63 (m, 2H), 1.08 (d, J 6.58, 3H). dC (100 MHz, CD3OD)
158.4, 148.2, 138.4, 129.9, 129.5, 129.0, 128.8, 127.5, 67.5,
60.8, 46.2, 29.7, 26.1, 19.3. m/z (HRMS) 330.1923 [M þ H]þ;
C17H24N5O2 requires 330.1924.
(10R,4R)-tert-Butyl-(10-(2-amino-1,4,5,6,7,8-
hexahydroimidazo[4,5-c]azepin-4-yl)ethyl)carbamate 8b
26
½aꢃD 8.9 (c 0.002 in EtOH). dH (400 MHz, CD3OD) 4.04–4.13
(m, 1H), 3.57 (d, J 5.5, 1H), 3.10–3.20 (m, 1H), 2.83–2.92
(m, 1H), 2.61–2.72 (m, 1H), 2.47–2.57 (m, 1H), 1.71–1.88
(m, 2H), 1.39 (s, 9H), 1.12 (d, J 6.8, 3H). dC (100 MHz, CD3OD)
157.5, 148.3, 129.9, 128.2, 80.0, 61.0, 47.8, 30.0, 28.7, 25.7,
17.1. m/z (HRMS) 318.1906 [M þ Na]þ; C14H25N5O2Na
requires 318.1900.
(10S,4S)-Benzyl (10-(2-Amino-1,4,5,6,7,8-
hexahydroimidazo[4,5-c]azepin-4-yl)ethyl)carbamate 8g
26
½aꢃD ꢀ1.2 (c 0.018 in EtOH). dH (400 MHz, CD3OD) 7.37–7.23
(m, 5H), 5.02 (s, 2H), 424–4.12 (m, 1H), 3.63 (d, J 4.6, 1H),
3.19–3.07 (m, 1H), 2.89–2.77 (m, 1H), 2.71–2.59 (m, 1H),
2.56–2.47 (m, 1H), 1.86–1.70 (m, 2H), 1.14 (d, J 6.9, 3H). dC
(100 MHz, CD3OD) 157.9, 148.4, 138.3, 130.3, 129.4, 128.9,
128.7, 128.0, 67.3, 60.9, 47.9, 30.0, 25.5, 16.9. m/z (HRMS)
330.1923 [M þ H]þ; C17H24N5O2 requires 330.1924.
(10S,4R)-tert-Butyl-(10-(2-amino-1,4,5,6,7,8-
hexahydroimidazo[4,5-c]azepin-4-yl)-20-phenylethyl)
carbamate 7c
½aꢃ2D6 12.7 (c 0.005 in EtOH). dH (400 MHz, CD3OD) 7.09–7.26
(m, 5H), 4.02–4.15 (m, 1H), 3.63 (d, J 8.2, 1H), 3.17–3.25
(m, 1H), 2.77–2.98 (m, 3H), 2.48–2.74 (m, 2H), 1.65–1.93
(m, 2H), 1.26 (s, 9H); dC (100 MHz, [D6]DMSO) dC 154.5,
146.1, 139.6, 128.8, 127.5, 125.2, 77.0, 58.2, 54.5, 46.9, 36.5,
28.9, 27.9, 23.5. m/z (HRMS) 394.2214 [M þ Na]þ;
C20H29N5O2Na requires 394.2213.
(10S, 4R)-Ethyl (10-(2-Amino-1,4,5,6,7,8-hexahydroimidazo
[4,5-c]azepin-4-yl)ethyl)carbamate 7h
½aꢃ2D6 18.2 (c 0.095 in EtOH). dH (400 MHz, CD3OD) 4.13–3.95
(m, 2H), 3.53 (d, J 8.8, 1H), 3.18–3.08 (m, 1H), 2.95–2.87
(m, 1H), 2.69–2.49 (m, 2H), 1.86–1.62 (m, 2H), 1.22 (t, J 7.1,
3H), 1.07 (d, J 6.6, 3H). dC (100 MHz, CD3OD) 158.7, 148.2,
130.0, 127.5, 61.8, 60.8, 46.2, 29.7, 26.2, 19.4, 15.0. m/z
(HRMS) 268.1768 [M þ H]þ; C12H22N5O2 requires 268.1768.
(10S,4R)-tert-Butyl-(10-(2-amino-1,4,5,6,7,8-
hexahydroimidazo[4,5-c]azepin-4-yl)-20-methylpropyl)
carbamate 7d
(10S,4S)-Ethyl (10-(2-Amino-1,4,5,6,7,8-hexahydroimidazo
[4,5-c]azepin-4-yl)ethyl)carbamate 8h
26
26
½aꢃD 22.3 (c 0.060 in EtOH). dH (400 MHz, CD3OD) 3.77 (dd,
½aꢃD ꢀ9.8 (c 0.025 in EtOH). dH (400 MHz, CD3OD) 4.20–4.11
J 8.6, 4.3, 1H), 3.68 (d, J 8.6, 1H), 3.12–3.22 (m, 1H), 2.83–2.91
(m, 1H), 2.62–2.72 (m, 1H), 2.48–2.57 (m, 1H), 1.64–1.83
(m, 3H), 1.43 (s, 9H), 0.88 (d, J 3.1, 3H), 0.86 (d, J 3.2, 3H).
dC (100 MHz, CD3OD) 158.6, 148.0, 129.5, 128.2, 80.0, 57.5,
57.0, 46.3, 30.2, 29.8, 28.8, 26.3, 21.3, 17.1. m/z (HRMS)
346.2206 [M þ Na]þ; C16H29N5O2Na requires 346.2213.
(m, 1H), 4.02 (q, J 7.01, 1H), 3.61 (d, J 5.12, 1H), 3.20–3.09 (m,
1H), 2.90–2.81 (m, 1H), 2.72–2.61 (m, 1H), 2.58–2.47 (m, 1H),
1.88–1.71 (m, 2H), 1.19 (t, J 7.01, 3H), 1.13 (d, J 6.86, 3H).
dC (100 MHz, CD3OD) 158.3, 148.5, 130.4, 128.1, 61.8, 61.1,
48.1, 30.2, 25.6, 17.0, 15.1. m/z (HRMS) 268.1768 [M þ H]þ;
C12H22N5O2 requires 268.1768.
(10R,4S)-(10-Aminoethyl)-1,4,5,6,7,8-hexahydroimidazo
[4,5-c]azepin-2-amine 9
(10R,4S)-tert-Butyl-(10-(2-amino-1,4,5,6,7,8-
hexahydroimidazo[4,5-c]azepin-4-yl)-20-methylpropyl)
carbamate 7e
Compound 7b (30 mg, 10 mmol) was dissolved in TFA/DCM
(3 mL, 1 : 1) and the reaction mixture was heated at 408C for 3 h,
after which the solvent was removed under reduced pressure,
leaving a light-brown solid, which was purified by column
chromatography (basic alumina) using a gradient of 5 : 95–
40 : 60 (MeOH/DCM saturated with ammonia) yielding the
deprotected azepinamine 9 (17 g, 85 %) as a thick colourless oil.
26
½aꢃD ꢀ21.4 (c 0.032 in EtOH). dH (400 MHz, CD3OD) 3.77
(dd, J 8.6, 4.2, 1H), 3.68 (d, J 8.9, 1H), 3.12–3.22 (m, 1H), 2.83–
2.91 (m, 1H), 2.62–2.72 (m, 1H), 2.48–2.57 (m, 1H), 1.64–1.83
(m, 3H), 1.43 (s, 9H), 0.88 (d, J 3.2, 3H), 0.86 (d, J 3.2, 3H).
dC (100 MHz, CD3OD) 158.7, 148.0, 129.6, 128.3, 80.0, 57.5,
57.0, 46.3, 30.2, 29.8, 28.8, 26.3, 21.3, 17.1. m/z (HRMS)
346.2211 [M þ Na]þ; C16H29N5O2Na requires 346.2213.
26
½aꢃD ꢀ14.9 (c 0.013 in EtOH). dH (400 MHz, CD3OD) 3.9
(d, J 9.4, 1H), 3.62–3.72 (m, 1H), 3.15–3.24 (m, 1H), 3.04–3.13
(m, 1H), 2.59–2.79 (m, 2H), 1.85–1.96 (m, 1H), 1.64–1.77
(m, 1H), 1.29 (d, J 6.6, 3H). dC (100 MHz, CD3OD) 147.8,
126.4, 122.7, 57.0, 45.1, 29.0, 24.6, 16.5. m/z (HRMS) 196.1560
[M þ H]þ; C9H18N5 requires 196.1562.
(10S,4R)-tert-Butyl-(10-(2-amino-1,4,5,6,7,8-
hexahydroimidazo[4,5-c]azepin-4-yl)-30-methylbutyl)
carbamate 7f
26
½aꢃD 5.6 (c 0.009 in EtOH). dH (400 MHz, CD3OD) 3.91–4.01
(10R,4R)-4-(10-Aminoethyl)-1,4,5,6,7,8-hexahydroimidazo
[4,5-c]azepin-2-amine 11
(m, 1H), 3.48 (d, J 8.3, 1H), 3.20–3.27 (m, 1H), 2.84–2.95
(m, 1H), 2.59–2.71 (m, 1H), 2.49–2.57 (m, 1H), 1.51–1.89
(m, 4H), 1.43 (s, 9H), 1.15–1.26 (m, 1H), 0.88 (d, J 6.7, 3H), 0.83
(d, J 6.4, 3H). dC (100 MHz, CD3OD) 158.3, 148.0, 129.4, 127.9,
79.9, 60.7, 51.1, 46.6, 43.3, 29.6, 28.8, 26.2, 24.2, 22.0. m/z
(HRMS) 360.2376 [M þ Na]þ; C17H31N5O2Na requires
360.2369.
Compound 8b (30 mg, 10 mmol) was dissolved in TFA/DCM
(3 mL, 1 : 1) and the reaction mixture was heated at 408C for
3 h, after which the solvent was removed under reduced
pressure, leaving a light-brown solid, which was purified by
column chromatography (basic alumina) using a gradient of

190
S. R. Shengule and P. Karuso
5 : 95–40 : 60 (MeOH/DCM saturated with ammonia) yielding
the deprotected azepinamine 11 (17 g, 89 %) as a thick colour-
less oil. ½aꢃ2D6 2.4 (c 0.008 in EtOH). dH (400 MHz, CD3OD) 4.21
(d, J 5.4, 1H), 3.85–3.94 (m, 1H), 3.07–3.16 (m, 1H), 2.73–2.85
(m, 1H), 2.60–2.70 (m, 1H), 1.85–2.02 (m, 1H), 1.33 (d, J 6.6,
3H). dC (100 MHz, CD3OD) dC 148.7, 129.0, 116.8, 55.6, 46.1,
25.3, 23.2, 15.7. m/z (HRMS) 196.1559 [M þ H]þ; C9H18N5
requires 196.1562.
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(10R,10aS)-2-Amino-10-methyl-4,5,6,9,10,10a-
hexahydrodiimidazo[1,5-a:40,50-c]azepine-8(3H)-one 10
(c) I. M. Piper, D. B. MacLean, R. Faggiani, C. J. L. Lock,
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G. A. Bhat, Ind. J. Chem. B 1977, 15B, 629.
To a stirred solution of 9 (16.0 mg, 0.08 mmol) in dry DMF
(3 mL) was added 1,10-carbonyldiimidazole (16.0 mg,
0.09 mmol) and the reaction mixture heated at 1008C for 2 h
under an inert atmosphere, after which solvent was removed
under reduced pressure and the dark-brown residue obtained
subjected to flash chromatography (silica; gradient 5 : 95–
20 : 80 MeOH/DCM saturated with ammonia) affording imi-
26
dazolidinone 10 (8 mg, 45 %) as a pale-yellow powder. ½aꢃD
13.4 (c 0.004 in EtOH). dH (600 MHz, [D6]DMSO) 6.38 (s, 1H),
4.97 (s, 2H), 3.98 (d, J 6.1, 1H), 3.91–3.86 (m, 1H), 3.70–3.65
(m, 1H), 2.71–2.65 (m, 1H), 2.57–2.51 (m, 1H), 2.48–2.42
(m, 1H), 1.81–1.75 (m, 1H), 1.58–1.50 (m, 1H), 1.23 (d, J 6.1,
3H). dC (100 MHz, CD3OD) 162.8, 149.5, 132.4, 129.8, 64.2,
52.2, 44.1, 28.0, 24.9, 22.0. m/z (HRMS) 222.1347 [M þ H]þ;
C10H16N5O requires 222.1355.
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(10R,10aR)-2-Amino-10-methyl-4,5,6,9,10,10a-
hexahydrodiimidazo[1,5-a:40,50-c]azepine-8(3H)-one 12
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To a stirred solution of 11 (12 mg, 0.06 mmol) in dry DMF
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0.07 mmol) and the reaction mixture heated at 1008C for 2 h
under an inert atmosphere, after which solvent was removed
under reduced pressure and the dark-brown residue obtained
subjected to flash chromatography (silica; gradient 5 : 95–
20 : 80 MeOH/DCM saturated with ammonia) affording imida-
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doi:10.1021/CR010212U
26
zolidinone 12 (7 mg, 53 %) as a pale-yellow powder. ½aꢃD 5.2
(c 0.003 in EtOH). dH (600 MHz, [D6]DMSO) 6.30 (s, 1H), 4.94
(s, 2H), 4.45 (d, J 7.1, 1H), 3.92–3.82 (m, 1H), 3.68–3.59 (m,
1H), 2.37–2.65 (m, 3H), 1.92–1.81 (m, 1H), 1.59–1.48 (m, 1H),
0.84 (d, J 6.4, 3H). dC (obtained from HMBC and HSQC)
(100 MHz, [D6]DMSO) 148.5, 59.9, 48.9, 40.6, 27.2, 23.2,
16.3. m/z (HRMS) 222.1354 [M þ H]þ, C10H16N5O requires
222.1355.
Supplementary Material
1D and 2D spectra are available on the Journal’s website.
(i) B. E. A. Burm, C. Gremmen, M. J. Wanner, G. J. Koomen,
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