8,9,10,10a-tetrahydro-6H-tetrazolo[1,5-a]pyrrolo[2,1-c]pyrazines: New heterocyclic frameworks generated by an Ugi-type multicomponent reaction

Article abstract of DOI:10.1055/s-2006-950219

A one-pot, Ugi-type three-component coupling process between an aldehyde, an isocyanide and proline tetrazole is reported, leading to new heterocyclic structures in good to excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950219

PAPER
3215
8,9,10,10a-Tetrahydro-6H-tetrazolo[1,5-a]pyrrolo[2,1-c]pyrazines: New Hete-
rocyclic Frameworks Generated by an Ugi-Type Multicomponent Reaction
New
H
eterocyclic
i
Framew
l
orks
G
i
e
nerat
u
ed by an Ugi
s
-Type Multicom
F
ponent Reacti
ron anckevičius, Deborah A. Longbottom, Richard M. Turner, Steven V. Ley*
University of Cambridge, Department of Chemistry, Lensfield Road, Cambridge, CB2 1EW, UK
Fax +44(1223)336442; E-mail: svl1000@cam.ac.uk
Received 10 July 2006
Abstract: A one-pot, Ugi-type three-component coupling process
between an aldehyde, an isocyanide and proline tetrazole is report-
ed, leading to new heterocyclic structures in good to excellent
yields.
Table 1 Proline and its Derivatives in Ugi-Type Coupling Reac-
tions
O
4
Key words: multicomponent reactions, heterocycles, tetrazole, Ugi
reaction, proline derivatives
H
1, 2 or 3, MeCN, r.t.
6–10
C
5
N
PMP
A multicomponent reaction (MCR) is one in which three
or more starting materials react together in a single vessel
to form a product which incorporates portions of all the
components.1 MCRs are highly efficient,2 not only due to
their convergent nature, but also because of superior atom
economy,3 and straightforward experimental procedures.
Entry Bifunctional Time Product
component (h)
Yield drb
(%)a
1
1
48
39c
1:1.6
H
O
O
N
∗
6 (major)
anti
7 (minor)
syn
MCRs involving isocyanides are among the most versa-
tile, in terms of the number and variety of compounds
which can be generated,4 and the Ugi reaction is one of the
most extensively utilised of these processes.5 In addition
to the diversity which can be generated in the Ugi reaction
alone, a range of alternative scaffolds have been created,
either by using secondary post-condensation reactions6 or
bifunctional components. For example, several groups
have reported the use of a- and b-amino acids in such cou-
plings to generate unique acyclic or heterocyclic struc-
tures.7–9 However, whilst a survey of the literature reveals
that (L)-proline (1, Figure 1) has been used in an Ugi-type
four-centre/three-component coupling,7a–f tetrazoles such
as proline tetrazole 2 and homotetrazole derivative 3, have
not been investigated in this context. It was thus thought
that new heterocyclic structures could potentially be gen-
erated by simply replacing the traditional a-amino acid
component with an a-amino tetrazole.
N
PMP
2
3
3
2
48
24
60
2.5:1
1.2:1
H
N
N
N
N
∗
N
N
8
PMP
67d
H
N
N
N
N
N
∗
9 (major)
syn
10 (minor)
anti
N
PMP
a Overall isolated yield of both isomers.
b Determined by 1H NMR spectroscopy of the crude product mixture.
c Isomers separated by column chromatography (26% major, 13% mi-
nor).
In our initial study, isovaleraldehyde (4) and p-methoxy-
phenyl isocyanide (5) were reacted together with either
proline (1), tetrazole 2 or homotetrazole 3 as the bifunc-
tional components (Table 1).
d Isomers separated by preparative HPLC (33% major, 29% minor).
Although diastereomeric ratios were moderate to low, it
was pleasing to find that, in each reaction, just two iso-
mers of product were formed (Table 1), where there are
potentially four. However, although the relationship of the
chiral centres could be ascertained, it was not possible to
assign the double-bond geometry of the products at this
point: a later study was to reveal this information.
N
N
N
OH
N
N
H
N
N
H
N
H
N
H
O
HN N
1
3
2
Figure 1 Proline and its tetrazole derivatives
In this initial screen, in the case of proline (Table 1, entry 1),
a moderate 39% overall yield of bicycles 6 and 7 was
found. More encouraging though was that homotetrazole
derivative 3 was also a successful substrate, providing the
SYNTHESIS 2006, No. 19, pp 3215–3223
Advanced online publication: 04.09.2006
DOI: 10.1055/s-2006-950219; Art ID: P08506SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
6

3216
V. Franckevičius et al.
PAPER
Table 2 Solvent Screena
desired product 8 in a good 60% yield (Table 1, entry 2),
despite the fact that formation of seven- rather than six-
membered ring was required. Finally, it was pleasing to
discover that the proline tetrazole itself gave the best yield
of products 9 and 10 (Table 1, entry 3), and therefore the
remainder of our investigations centred on the formation
of this unit.
N
N
H
N
H
N
N
18
N
HN
O
N
N
N
∗
r.t., 48 h
solvent
4
N
H
This new heterocyclic framework comprises a rigid 5–6–5-
fused core structure and two points of substitution (alde-
hyde and isocyanide), with potential application in medic-
inal chemistry and compound library synthesis. As
alluded to previously, it is important to note that there are
four possible products which may be formed in this reac-
tion (Figure 2): epimers of the chiral centre containing the
aldehyde substituent, and two double bond isomers, fur-
ther discussion of which follows later.
20
C
19
N
Entry
Solvent
MeOH
Et2O
Yield (%)b,c
drd
1
2
3
4
5
6
35
50
74
78
56
92
2.3:1
6.1:1
3.9:1
3.9:1
8.4:1
6.5:1
MeCN
THF
H
N
H
N
N
N
N
Toluene
CH2Cl2
N
N
N
N
N
R1
R1
H
H
a The (R)-enantiomer of the proline tetrazole was used (18).
N
N
R2
12
R2
11
b Isolated yield of both isomers.
c A small amount of the major isomer was isolated for full character-
isation.
H
N
H
N
N
d Determined by 1H NMR spectroscopy of the crude product mixture.
N
H
N
N
N
N
R1
N
R1
N
H
a solvent screen was carried out, with proline tetrazole 18,
benzyl isocyanide 19 and isovaleraldehyde 4 (Table 2).
N
N
R2
14
R2
13
Figure 2 Possible isomers in the Ugi coupling with tetrazole 2
It was found that diastereoselectivity and yield were
strongly affected by solvent. While methanol gave the
lowest yield (Table 2, entry 1),10 diethyl ether, acetonitrile
and tetrahydrofuran all provided moderate to good yields
and diastereoselectivities (Table 2, entries 2–4). Howev-
er, in terms of diastereoselectivity, the best results were
found in both toluene and dichloromethane (Table 2, en-
tries 5 and 6), although dichloromethane was considered
optimal, as the yield was excellent (92%) and the diaste-
reoselection good (6.5:1).
The reaction is an Ugi-type four-centre/three-component
coupling where the pyrrolidine and the tetrazole act as the
tethered bifunctional amine/acid component, together
with the aldehyde and isocyanide as the remaining two.
With respect to the reaction mechanism, it is plausible that
the iminium ion 15 is attacked by the isocyanide to give
intermediate 16 (Scheme 1), and ring closure would then
result in formation of product 17.
Having chosen dichloromethane as solvent, reaction
scope was next explored. Firstly, a range of isocyanides
were investigated (Table 3), and it was found that all reac-
tions were complete within 24 hours. Thus, all further re-
actions were also given this standard reaction time for
operational convenience.
Following this promising initial result, we turned our at-
tention to the optimisation of reaction conditions. Firstly,
N
N
N
N
N
N
H
2
HN
N
HN
N
– H2O
R1
The desired products were generally obtained in excellent
yields with moderate to good diastereoselectivity. The ex-
ceptions were the PMP example (Table 3, entry 1), which
gave a slightly lower yield (67%) and the tert-butyl exam-
ple (Table 3, entry 6), which cleanly provided a single iso-
mer in high yield (91%), directly from the reaction
mixture. p-Substituted phenyl isocyanides as well as ben-
zyl isocyanide provided the desired products as a mixture
of only two isomers (Table 3, entries 1–4), whilst interest-
ingly, cyclohexyl isocyanide afforded the desired product
as a mixture of three isomers (Table 3, entry 5), which
could potentially be epimers of the chiral centre contain-
ing the iso-butyl group, as well as double bond isomers.
15
O
C
N
R2
R1
H
H
N
N
N
N
N
N
N
HN
N
N
N
R1
∗
R1
∗
16
R2
N
R2
17
Scheme 1 Proposed reaction mechanism
Synthesis 2006, No. 19, 3215–3223 © Thieme Stuttgart · New York

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New Heterocyclic Frameworks Generated by an Ugi-Type Multicomponent Reaction
3217
Table 4 Aldehyde Scope
Table 3 Isocyanide Scope
N
N
H
N
N
N
H
N
H
N
N
N
2
H
N
HN
N
2
HN
O
N
N
N
N
N
N
∗
R
O
r.t., 24 h
CH2Cl2
r.t., 24 h
CH2Cl2
N
∗
N
4
H
R
H
N
R
C
23,26–29
C
N
9,10, 21–25
N
R
19
Entry
1
R
Product Yield
Ratio
Entry
1
R
Product Yield
Ratio
(%)a
of productsb
(%)b
of productsc
9c
67
1.2: 1: 0
23a
93
6.8: 1: 0
10d
2
3
26a
27a
71
83
9.4: 1.9: 1
6.7: 1.5: 1
MeO
2
3
21c
22e
90
93
2.1: 1: 0
1.7: 1: 0
Et2N
4
5
28a
29a
67
74
2.8: 1.2: 1
4.3: 1.4: 1
Cl
Ph
O
4
5
23c
24c
93
90
6.8: 1: 0
a Major isomer (syn).
b Isolated yield of all isomers.
c Determined by 1H NMR spectroscopy of the crude product mixture.
7.3: 2.3: 1
In order to determine the stereochemical outcome of these
reactions, NMR studies were conducted on 20 (major iso-
mer) and 25 (Figure 3), and it was interesting to observe
that the NOE data suggested contrasting results in each
case. For the benzyl substituted compound 20, a strong
6
25
91f
single isomer
a Isolated yield of all isomers.
b Determined by 1H NMR spectroscopy of the crude product mixture. NOE enhancement was found between the Ha and Hb pro-
c Major isomer (syn).
tons (Figure 3), suggesting that they are syn to one anoth-
er. No such enhancement was found in the tert-butyl case
d Minor isomer (anti).
e Mixture of isomers.
(25), suggesting that the protons are anti. In addition, an
NOE enhancement was seen between Ha and the tert-butyl
protons in 25, suggesting that the tert-butyl group is trans
to the tetrazole. In contrast, no NOE enhancement be-
tween Ha and the benzyl protons in 20 was observed, im-
plying that the benzyl substituent is cis to the tetrazole
moiety.
f Crude yield.
Having screened a range of isocyanides, the scope of al-
dehydes in the reaction was next investigated. It was
found that unsaturated aldehydes did not react under these
reaction conditions, a finding consistent with their re-
duced electrophilicity. Therefore, linear, branched and
more functionalised aldehydes were used in the same re-
action process and, pleasingly, most examples afforded
the desired products in good to excellent yield and moder-
ate to good selectivity (Table 4).
NOE
enhancement
Hb
no NOE
(4.2%)
N
enhancement
N
Hb
N
Ha
N
N
N
N
N
N
The best result was obtained with isovaleraldehyde (4),
which afforded the desired product in an excellent 93%
yield, with moderate selectivity, as a mixture of two iso-
mers (Table 4, entry 1). Each of the remaining aldehydes
led to the desired heterocyclic product as a mixture of
three isomers in good yields and moderate to good selec-
tivity (Table 4, entries 2–5), with cyclohexanecarboxalde-
hyde being the best yielding of the these examples
(Table 4, entry 3), and with hexanal showing the greatest
selectivity (Table 4, entry 2).
Ha
N
N
no NOE
enhancement
NOE
enhancement
(14.6%)
N
20
25
(single isomer)
(major isomer)
Figure 3 Stereochemical assignment by NMR
Synthesis 2006, No. 19, 3215–3223 © Thieme Stuttgart · New York

3218
V. Franckevičius et al.
PAPER
paratus, and are uncorrected. Preparatory HPLC techniques were
carried out on Agilent 1100 using a Hichrom KR100-5-250010 col-
umn.
Due to their crystalline nature, it was possible to obtain
X-ray crystal structures of both compounds and thus, un-
ambiguously confirm the original stereochemical assign-
ment (Figure 4).11 For the benzyl case 20, this places the
iso-butyl group in the pseudo-equatorial position and the
benzyl group cis to the tetrazole. In the tert-butyl case 25
it appears that the extra steric bulk of this group forces it
to be placed trans to the tetrazole. This in turn causes such
a large steric clash with the iso-butyl group that it is forced
to occupy the pseudo-axial position on the ring, placing
protons Ha and Hb anti to one another.
The numbering schemes used in the characterization data that fol-
low are shown in Figure 5.
To a suspension of proline tetrazole 2 or 18 (84 mg, 0.6 mmol) in
CH2Cl2 (4 mL) was added the isocyanide (0.6 mmol) followed by
the aldehyde (0.6 mmol). The resulting mixture was stirred at r.t. for
24 h. The reaction mixture was diluted with EtOAc (20 mL),
washed with aq. NaHCO3 (2 × 20 mL) and brine (20 mL). The or-
ganic layer was dried (MgSO4), concentrated in vacuo, and the res-
idue was purified by flash column chromatography.
(4S,8aS)-3-(4-Methoxyphenylimino)hexahydro-4-iso-butylpyr-
rolo[2,1-c][1,4]oxazin-1-one (6); Major Isomer
25
Dark-yellow solid; mp 40–42 °C; Rf 0.09 (PE–EtOAc, 4:1); [a]D
–7.3 (c 0.87, CHCl3).
IR (film): 2957, 1775 (C=O), 1690 (C=N), 1606, 1505 cm–1.
1H NMR (600 MHz, CDCl3): d = 7.11 (2 H, d, J = 8.8 Hz, 2 × H-
14), 6.85 (2 H, d, J = 8.8 Hz, 2 × H-13), 4.07 (1 H, dd, J = 9.2, 5.0
Hz, H-5), 3.79 (3 H, s, H3-16), 3.76 (1 H, app t, J = 8.1 Hz, H-9),
3.17–3.13 (1 H, m, Ha-6), 2.75 (1 H, app q, J = 8.6 Hz, Hb-6), 2.48–
2.40 (1 H, m, Ha-4), 2.12–2.03 (1 H, m, Hb-4), 1.92–1.83 (3 H, m,
H-3 and H2-7), 1.68–1.60 (2 H, m, H2-8), 1.01 (3 H, d, J = 6.7 Hz,
H3-1), 0.97 (3 H, d, J = 6.6 Hz, H3-2).
13C NMR (150 MHz, CDCl3): d = 169.7 (C-11), 157.1 (C-15), 149.5
(C-10), 136.5 (C-12), 124.7 (C-14), 113.9 (C-13), 57.4 (C-9), 56.6
(C-5), 55.4 (C-16), 52.5 (C-6), 40.4 (C-8), 30.0 (C-4), 24.8 (C-3),
23.6 (C-7), 22.6 (C-1 or C-2), 22.2 (C-1 or C-2).
Figure 4 Crystal structures of 20 and 25
In summary, a facile method for the synthesis of a new
heterocycle class has been developed. All three compo-
nents were used in equimolar amounts and reactions pro-
ceeded at room temperature. The scope of the reaction has
been successfully demonstrated by examining a range of
isocyanide and aldehyde components, and structures of
two examples have been determined by NMR and X-ray
analysis. In addition to applications in library synthesis,
these new heterocycles broaden the scaffolds that are ac-
cessible through Ugi reactions and have potential in me-
dicinal chemistry.
No NOE enhancement observed between H-5 and H-9.
HRMS (ESI): m/z [M + H]+ calcd for C18H24N2O3: 317.1865; found:
317.1856.
(4R,8aS)-3-(4-Methoxyphenylimino)hexahydro-4-iso-butylpyr-
rolo[2,1-c][1,4]oxazin-1-one (7); Minor Isomer
Yellow solid; mp 37–39 °C; Rf 0.18 (PE–EtOAc, 4:1); [a]D25 +2.2
(c 0.45, CHCl3).
IR (film): 2955, 1775 (C=O), 1693 (C=N), 1506 cm–1.
1H NMR (600 MHz, CDCl3): d = 7.07 (2 H, d, J = 8.8 Hz, 2 × H-
14), 6.84 (2 H, d, J = 8.8 Hz, 2 × H-13), 4.00 (1 H, dd, J = 9.1, 4.5
Hz, H-5), 3.80–3.74 (4 H, m, H-9 and H3-16), 2.94–2.88 (1 H, m,
Ha-6), 2.57 (1 H, app q, J = 8.4 Hz, Hb-6), 2.41–2.33 (1 H, m, Ha-4),
2.15–2.09 (1 H, m, Hb-4), 1.96–1.84 (4 H, m, H-3, H2-7 and Ha-8),
1.74–1.68 (1 H, m, Hb-8), 1.00 (3 H, d, J = 6.4 Hz, H3-1), 0.97 (3 H,
d, J = 6.2 Hz, H3-2).
13C NMR (150 MHz, CDCl3): d = 169.6 (C-11), 157.0 (C-15), 149.1
(C-10), 136.7 (C-12), 124.4 (C-14), 113.9 (C-13), 63.4 (C-5), 56.6
(C-9), 55.4 (C-16), 46.4 (C-6), 38.5 (C-8), 28.7 (C-4), 24.4 (C-3),
23.2 (C-2), 23.2 (C-7), 22.1 (C-1).
All reactions were carried out under an atmosphere of argon in
oven-dried glassware. Petroleum ether (PE) used refers to the 40–
60 °C boiling point fraction of petroleum. Diethyl ether and tetrahy-
drofuran were distilled over calcium hydride and lithium aluminium
hydride; dichloromethane, methanol, acetonitrile and toluene were
distilled over calcium hydride. Proline tetrazole 2 was prepared by
a literature procedure.12 All other reagents and solvents were used
as supplied. Flash column chromatography was carried out using
Merck Kieselgel (230–400 mesh). 1H NMR spectra were recorded
on a Bruker DRX-600 spectrometer. Where coincident coupling
constants were observed in the NMR spectrum, the apparent (app)
multiplicity of the proton concerned is reported. For spectra record-
ed in CDCl3, residual protic solvent CHCl3 (dH = 7.26 ppm) was
used as an internal standard. 13C NMR spectra were recorded on the
same spectrometer at 150 MHz, using central resonance of CDCl3
(dC = 77.0 ppm) as the internal reference. Accurate mass data were
obtained on Micromass Q-TOF by electrospray ionisation (ESI).
Optical rotations were measured on a Perkin Elmer 343 polarimeter
and [d]D values are reported in 10–1degcm2g–1; concentration (c) is
in g/100 mL. Infra-red spectra were recorded on a Perkin Elmer
Spectrum One FT-IR spectrometer. Samples were prepared as a
neat film. Melting points were measured on a Reichert hot stage ap-
NOE enhancement observed between H-5 and H-9 (2.7%).
HRMS (ESI): m/z [M + H]+ calcd for C18H24N2O3: 317.1865; found:
317.1860.
(6SR,10aS)-5-(4-Methoxyphenylimino)-6-iso-butyl-8,9,10,10a-
tetrahydrotetrazolo[1,5-a]pyrrolo[2,1-d]-1,5-diazepane (8);
Mixture of Isomers
Brown solid; Rf 0.21 (PE–EtOAc, 1:1).
IR (film): 2958, 1657 (C=N), 1579, 1501 cm–1.
1H NMR (600 MHz, CDCl3): (inseparable mixture of isomers, mi-
nor isomer starred) d = 6.97 (2 H, d, J = 9.0 Hz, 2 × H-14), 6.95
(2 H, d, J = 9.0 Hz, 2 × H-15), 6.73 (2 H*, d, J = 8.8 Hz, 2 × H*-14),
6.62 (2 H*, d, J = 8.9 Hz, 2 × H*-15), 4.26 (1 H, dd, J = 9.1, 5.5 Hz,
Synthesis 2006, No. 19, 3215–3223 © Thieme Stuttgart · New York

PAPER
New Heterocyclic Frameworks Generated by an Ugi-Type Multicomponent Reaction
3219
8
7
8
7
8
7
8
7
H
N
9
H
9
H
9
10
6
6
9
10
H
10
2
3
O
2
3
O
6
6
11
N
N
10
2
2
3
N
N
N
N
5
N
5
5
O
11
O
N
N
5
N
12
1
N
11
1
11
4
4
N
3
H
13
H
13
1
4
H
4
14
15
N
12
N
12
1
H
13
14
15
13
14
15
15
16
N
12
14
15
13
13
14
O
O
13
14
O
14
O
14
6
7
8
9
17
16
16
16
8
7
8
7
9
8
H
7
6
4
9
H
8
7
10
2
6
9
N
N
H
N
10
N
2
6
N
9
H
10
N
2
N
N
N
6
5
10
N
N
2
N
11
N
5
N
N
3
N
11
5
1
N
13
3
N
H
1
5
4
3
N
11
1
11
H
N
4
N
12
13
3
H
13
1
N
12
4
14
15
H
N
12
13
14
15
N
12
14
15
16
14
15
14
15
13
13
N
17
10
20
21
22
14
O
13
14
Cl
14
16
16
17
16
8
9
10
8
7
8
7
H
9
H
8
7
7
6
4
11
9
10
H
N
N
2
N
N
6
9
N
6
H
N
10
2
6
N
2
N
4
N
10
N
5
2
3
N
N
N
N
11
N
N
5
3
1
12
N
1
N
5
3
5
H
N
H
3
N
11
1
11
4
N
N
H
1
13
14
12
13
4
H
N
12
14
13
N
12
15
16
15
16
15
16
14
15
13
14
13
18
23
24
25
26
15
17
17
16
9
6
9
7
10
11H
12
10
11
H
9
8
H
5
3
8
8
12
N
N
N
N
N
4
N
N
7
7
N
N
N
5
2
7
8
N
10
N
6
N
13
1
N
3
1
6
N
6
13
H
H
2
H
H
4
9
N
5
N
O
N
N
H
2
11
12
12
13
14
15
5
4
14
15
N
11
3
14
15
1
4
13
14
13
14
3
2
16
17
3
16
17
16
17
16
17
14
N
2
10
15
N
16
15
18
18
1
30
27
28
29
Figure 5
H-5), 4.11 (1 H*, dd, J = 10.0, 5.3 Hz, H*-5), 3.83 (3 H, s, H3-17),
3.73 (3 H*, s, H*3-17), 3.64 (1 H*, app t, J = 6.5 Hz, Ha*-6), 3.48
(1 H, dd, J = 15.5, 2.0 Hz, Ha-10), 3.40–3.29 (1 H and 1 H*, m, H-
9 and Ha*-10), 3.25 (1 H*, app dt, J = 5.4, 8.9 Hz, Hb*-6), 3.08 (1 H,
app dt, J = 4.8, 8.6 Hz, Ha-6), 3.05–2.97 (2 H*, m, H*-9 and Hb*-
10), 2.95 (1 H, dd, J = 15.5, 11.0 Hz, Hb-10), 2.73 (1 H, dd, J = 15.3,
8.6 Hz, Hb-6), 2.22–2.06 (1 H and 1 H*, m, Ha-8 and Ha*-8), 1.96–
1.85 (1 H, m, Ha-7), 1.83–1.75 (1 H, m, Hb-7), 1.72–1.60 (1 H and
2 H*, m, Hb-8, H*-3 and Hb*-8), 1.55 (1 H*, app dt, J = 7.0, 14.9
Hz, Ha*-7), 1.48–1.35 (1 H and 1 H*, m, H-3 and Hb*-7), 1.33–1.22
(1 H and 1 H*, m, Ha-4 and Ha*-4), 1.15–1.08 (1 H*, m, Hb*-4),
1.07–1.00 (1 H, m, Hb-4), 0.98 (3 H*, d, J = 6.6 Hz, H*3-1), 0.86
(3 H*, d, J = 6.6 Hz, H*3-2), 0.71 (3 H, d, J = 6.6 Hz, H3-1), 0.58
(3 H, d, J = 6.6 Hz, H3-2).
13C NMR (150 MHz, CDCl3): d = 157.6 (C*-16), 157.6 (C-16),
153.4 (C-12), 153.2 (C*-11), 152.7 (C-11), 145.3 (C*-12), 139.0
(C-13), 138.3 (C*-13), 121.9 (C*-15), 121.4 (C-15), 114.5 (C-14),
114.3 (C*-14), 62.3 (C*-5), 55.5 (C-17), 55.3 (C*-17), 54.7 (C-5),
51.5 (C-9), 51.4 (C*-9), 51.2 (C-6), 50.8 (C*-6), 34.4 (C*-4), 34.2
(C-4), 32.1 (C-8), 32.0 (C*-8), 29.8 (C-10), 28.7 (C*-10), 25.0 (C*-
3), 24.7 (C-3), 23.1 (C*-1), 22.9 (C-1), 21.9 (C-2), 21.8 (C*-2), 21.2
(C-7), 20.9 (C*-7).
HRMS (ESI): m/z [M + H]+ calcd for C19H26N6O: 355.2246; found:
355.2255.
Synthesis 2006, No. 19, 3215–3223 © Thieme Stuttgart · New York

3220
V. Franckevičius et al.
PAPER
(6R,10aS)-5-(4-Methoxyphenylimino)-6-iso-butyl-8,9,10,10a-
tetrahydro-6H-tetrazolo[1,5-a]pyrrolo[2,1-c]pyrazine (9);
Major Isomer
HRMS (ESI): m/z [M + H]+ calcd for C18H24N6: 325.2141; found:
325.2128.
White crystalline solid; mp 122–124 °C; Rf 0.44 (PE–EtOAc, 1:1);
(Z,6R,10aS)-5-(4-N,N-Diethylaminophenyl)imino-6-iso-butyl-
8,9,10,10a-tetrahydro-6H-tetrazolo[1,5-a]pyrrolo[2,1-c]pyra-
zine (21); Major Isomer
[a]D25 –202.8 (c 0.33, CHCl3).
IR (film): 2954, 1698 (C=N), 1607, 1503 cm–1.
Bright-yellow foam; mp 121–123 °C; Rf 0.40 (PE–EtOAc, 1:1);
1H NMR (600 MHz, CDCl3): d = 6.86 (2 H, d, J = 8.7 Hz, 2 × H-
13), 6.73 (2 H, d, J = 8.4 Hz, 2 × H-14), 4.77 (1 H, br s, H-9), 3.95
(1 H, br s, H-5), 3.81 (3 H, s, H3-16), 3.11 (1 H, br s, Ha-6), 2.60–
2.47 (2 H, m, Hb-6 and Ha-8), 2.40–2.32 (1 H, m, Hb-8), 2.11–1.88
(3 H, m, H-3, Ha-4 and Ha-7), 1.87–1.70 (2 H, m, Hb-4 and Hb-7),
1.02 (3 H, app s, H3-1), 0.98 (3 H, app s, H3-2).
13C NMR (150 MHz, CDCl3): d = 156.9 (C-15), 156.1 (C-10), 140.3
(C-11), 139.7 (C-12), 120.4 (C-14), 114.3 (C-13), 58.6 (C-5), 57.0
(C-9), 55.4 (C-16), 44.6 (C-6), 37.5 (C-4), 29.9 (C-8), 24.5 (C-3),
23.4 (C-2), 23.0 (C-7), 21.8 (C-1).
[a]D25 –811.1 (c 0.57, CHCl3).
IR (film): 2954, 2934, 2847, 1697 (C=N), 1606 cm–1.
1H NMR (600 MHz, CDCl3): d = 6.76 (2 H, d, J = 8.8 Hz, 2 × H-13
or 2 × H-14), 6.62 (2 H, d, J = 8.7 Hz, 2 × H-13 or 2 × H-14), 4.82–
4.71 (1 H, m, H-9), 3.89 (1 H, br s, H-5), 3.34 (4 H, q, J = 7.1 Hz,
2 × H2-16), 3.10–3.04 (1 H, m, Ha-6), 2.59–2.51 (2 H, m, Hb-6 and
Ha-8), 2.37–2.29 (1 H, m, Hb-8), 2.02–1.89 (3 H, m, H-3, Ha-4 and
Ha-7), 1.82–1.70 (2 H, m, Hb-4 and Hb-7), 1.15 (6 H, t, J = 7.0 Hz,
2 × H3-17), 1.03–0.91 (6 H, m, H3-1 and H3-2).
13C NMR (150 MHz, CDCl3): d = 156.0 (C-10), 145.9 (C-15), 134.3
(C-12), 121.9 (C-13 or C-14), 112.1 (C-13 or C-14), 112.1 (C-11),
58.8 (C-5), 56.9 (C-9), 44.7 (C-6), 44.5 (C-16), 37.6 (C-4), 30.0 (C-
8), 24.6 (C-3), 23.3 (C-1), 23.1 (C-7), 21.9 (C-2), 12.6 (C-17).
NOE enhancement observed between H-5 and H-9 (3.7%).
HRMS (ESI): m/z [M + Na]+ calcd for C18H24N6O: 363.1904;
found: 363.1895.
NOE enhancement observed between H-5 and H-9 (4.4%).
HRMS (ESI): m/z [M + H]+ calcd for C21H31N7: 382.2719; found:
382.2708.
(6S,10aS)-5-(4-Methoxyphenylimino)-6-iso-butyl-8,9,10,10a-
tetrahydro-6H-tetrazolo[1,5-a]pyrrolo[2,1-c]pyrazine (10); Mi-
nor Isomer
White crystalline solid; mp 139–141 °C; Rf 0.32 (PE–EtOAc, 1:1);
[a]D25 +162 (c 0.15, CHCl3).
(6RS,10aS)-5-(4-Chlorophenyl)imino-6-iso-butyl-8,9,10,10a-
tetrahydro-6H-tetrazolo[1,5-a]pyrrolo[2,1-c]pyrazine (22);
Mixture of Isomers
Yellow solid; Rf 0.12 (PE–EtOAc, 4:1).
IR (film): 2933, 1696 (C=N), 1605 cm–1.
1H NMR (600 MHz, CDCl3): (inseparable mixture of isomers, mi-
nor isomer starred) d = 7.37 (2 H*, d, J = 8.5 Hz, 2 × H*-13 or
2 × H*-14), 7.27 (2 H, d, J = 8.6 Hz, 2 × H-13 or 2 × H-14), 6.85
(2 H*, d, J = 8.5 Hz, 2 × H*-13 or 2 × H*-14), 6.69 (2 H, d, J = 8.2
Hz, 2 × H-13 or 2 × H-14), 4.80–4.68 (1 H and 1 H*, m, H-9 and
H*-9), 4.06 (1 H*, dd, J = 11.0, 4.6 Hz, H*-5), 4.02–3.96 (1 H, m,
H-5), 3.14–3.05 (1 H and 1 H*, m, Ha-6 and Ha*-6), 2.57–2.31 (3 H
and 3 H*, m, Hb-6, H2-8, Hb*-6 and H*2-8), 2.05–1.89 (3 H and
1 H*, m, H-3, Ha-4, Ha-7 and Ha*-7), 1.85–1.71 (2 H and 2 H*, m,
Hb-4, Hb-7, H*-3 and Hb*-7), 1.55 (1 H*, ddd, J = 14.8, 10.8, 4.4
Hz, Ha*-4), 1.26–1.19 (1 H*, m, Hb*-4), 1.01 (3 H, app s, H3-1),
0.97 (3 H, app s, H3-2), 0.77 (3 H*, d, J = 6.7 Hz, H*3-1), 0.64
(3 H*, d, J = 6.5 Hz, H*3-2).
IR (film): 2956, 1680 (C=N), 1607, 1504 cm–1.
1H NMR (600 MHz, CDCl3): d = 6.94 (2 H, d, J = 8.7 Hz, 2 × H-
13), 6.88 (2 H, d, J = 8.7 Hz, 2 × H-14), 4.71 (1 H, dd, J = 8.3, 1.7
Hz, H-9), 4.18 (1 H, dd, J = 10.7, 4.6 Hz, H-5), 3.83 (3 H, s, H3-16),
3.08 (1 H, dt, J = 2.5, 8.2 Hz, Ha-6), 2.57–2.49 (2 H, m, Hb-6 and
Ha-8), 2.45–2.39 (1 H, m, Hb-8), 2.01–1.91 (1 H, m, Ha-7), 1.82–
1.73 (2 H, m, H-3 and Hb-7), 1.54 (1 H, ddd, J = 14.6, 10.8, 4.4 Hz,
Ha-4), 1.32–1.25 (1 H, m, Hb-4), 0.77 (3 H, d, J = 6.7 Hz, H3-1),
0.68 (3 H, d, J = 6.5 Hz, H3-2).
13C NMR (150 MHz, CDCl3): d = 157.3 (C-15), 154.8 (C-10), 150.1
(C-11), 138.5 (C-12), 120.8 (C-13), 114.6 (C-14), 55.5 (C-16), 54.1
(C-5), 51.2 (C-6), 51.0 (C-9), 40.1 (C-4), 29.8 (C-8), 24.5 (C-3),
23.0 (C-2), 22.6 (C-7), 21.1 (C-1).
No NOE enhancement observed between H-5 and H-9.
HRMS (ESI): m/z [M + Na]+ calcd for C18H24N6O: 363.1904;
found: 363.1892.
13C NMR (150 MHz, CDCl3): d = 156.0 (C*-10), 154.8 (C-10),
150.7 (C*-11), 145.4 (C-12 or C-15), 143.9 (C*-12 or C*-15), 141.4
(C-11), 130.7 (C*-12 or C*-15), 129.7 (C-12 or C-15), 129.5 (C*-
13 or C*-14), 129.1 (C-13 or C-14), 120.6 (C*-13 or C*-14), 120.2
(C-13 or C-14), 58.5 (C-5), 57.0 (C-9), 54.2 (C*-5), 51.3 (C*-6),
50.9 (C*-9), 44.6 (C-6), 40.0 (C*-4), 37.4 (C-4), 29.7 (C-8), 29.7
(C*-8), 24.5 (C*-3), 24.5 (C-3), 23.3 (C-2), 22.9 (C*-2), 22.8 (C-7),
22.5 (C*-7), 21.7 (C-1), 21.0 (C*-1).
(Z,6S,10aR)-5-Benzylimino-6-iso-butyl-8,9,10,10a-tetrahydro-
6H-tetrazolo[1,5-a]pyrrolo[2,1-c]pyrazine (20); Major Isomer
White crystalline solid; mp 82–84 °C; Rf 0.55 (PE–EtOAc, 1:1);
[a]D25 –163 (c 0.135, CHCl3).
IR (film): 2960, 1711 (C=N), 1607 cm–1.
1H NMR (600 MHz, CDCl3): d = 7.47 (2 H, d, J = 7.5 Hz, 2 × H-
14), 7.38 (2 H, app t, J = 7.5 Hz, 2 × H-15), 7.27 (1 H, t, J = 7.5 Hz,
H-16), 5.35 (1 H, d, J = 18.0 Hz, Ha-12), 5.26 (1 H, d, J = 18.0 Hz,
Hb-12), 4.78 (1 H, dd, J = 8.3, 2.1 Hz, H-9), 3.93–3.88 (1 H, m, H-
5), 3.02 (1 H, app dt, J = 3.5, 8.5 Hz, Ha-6), 2.57–2.50 (1 H, m, Ha-
8), 2.39–2.33 (1 H, m, Hb-8), 2.29 (1 H, app q, J = 8.7 Hz, Hb-6),
2.05–1.99 (1 H, m, Ha-4), 1.98–1.89 (2 H, m, H-3 and Ha-7), 1.75–
1.68 (2 H, m, Hb-4 and Hb-7), 1.01 (3 H, d, J = 6.7 Hz, H3-1), 0.97
(3 H, d, J = 6.5 Hz, H3-2).
13C NMR (150 MHz, CDCl3): d = 156.1 (C-10), 140.0 (C-11), 139.6
(C-13), 128.4 (C-15), 127.3 (C-14), 126.9 (C-16), 58.9 (C-5), 57.1
(C-9), 54.5 (C-12), 44.5 (C-6), 37.8 (C-4), 29.8 (C-8), 24.6 (C-3),
23.3 (C-1), 22.8 (C-7), 22.0 (C-2).
HRMS (ESI): m/z [M + H]+ calcd for C17H21N6Cl: 345.1594; found:
345.1600.
(Z,6R,10aS)-5-Benzylimino-6-iso-butyl-8,9,10,10a-tetrahydro-
6H-tetrazolo[1,5-a]pyrrolo[2,1-c]pyrazine (23); Major Isomer
White crystalline solid; mp 81–84 °C; Rf 0.50 (PE–EtOAc, 1:1);
[a]D25 +144 (c 0.180, CHCl3).
IR (film): 2956, 1701 (C=N) cm–1.
1H NMR (600 MHz, CDCl3): d = 7.48 (2 H, d, J = 7.5 Hz, 2 × H-
14), 7.38 (2 H, app t, J = 7.7 Hz, 2 × H-15), 7.27 (1 H, t, J = 7.6 Hz,
H-16), 5.35 (1 H, d, J = 18.0 Hz, Ha-12), 5.26 (1 H, d, J = 18.0 Hz,
Hb-12), 4.78 (1 H, dd, J = 8.3, 2.1 Hz, H-9), 3.93–3.88 (1 H, m, H-
5), 3.02 (1 H, app dt, J = 3.5, 8.5 Hz, Ha-6), 2.57–2.50 (1 H, m, Ha-
NOE enhancement observed between H-5 and H-9 (4.2%).
Synthesis 2006, No. 19, 3215–3223 © Thieme Stuttgart · New York

PAPER
New Heterocyclic Frameworks Generated by an Ugi-Type Multicomponent Reaction
3221
8), 2.39–2.33 (1 H, m, Hb-8), 2.29 (1 H, app q, J = 8.6 Hz, Hb-6),
2.05–1.99 (1 H, m, Ha-4), 1.98–1.89 (2 H, m, H-3 and Ha-7), 1.75–
1.68 (2 H, m, Hb-4 and Hb-7), 1.01 (3 H, d, J = 6.7 Hz, H3-1), 0.97
(3 H, d, J = 6.3 Hz, H3-2).
13C NMR (150 MHz, CDCl3): d = 156.1 (C-10), 140.0 (C-11), 139.6
(C-13), 128.5 (C-15), 127.3 (C-14), 126.9 (C-16), 58.9 (C-5), 57.1
(C-9), 54.6 (C-12), 44.5 (C-6), 37.8 (C-4), 29.8 (C-8), 24.6 (C-3),
23.3 (C-1), 22.8 (C-7), 22.0 (C-2).
17), 5.35 (1 H, d, J = 18.1 Hz, Ha-13), 5.27 (1 H, d, J = 18.0 Hz, Hb-
13), 4.68 (1 H, dd, J = 8.1, 2.5 Hz, H-10), 3.81–3.76 (1 H, m, H-6),
2.98 (1 H, app dt, J = 4.1, 8.9 Hz, Ha-7), 2.58–2.50 (1 H, m, Ha-9),
2.38–2.32 (2 H, m, Hb-7 and Hb-9), 2.24–2.16 (1 H, m, Ha-5), 1.99–
1.91 (1 H, m, Ha-8), 1.84–1.70 (2 H, m, Hb-5 and Hb-8), 1.58–1.48
(2 H, m, H2-4), 1.42–1.31 (4 H, m, H2-2 and H2-3), 0.95–0.88 (3 H,
m, H3-1).
13C NMR (150 MHz, CDCl3): d = 156.0 (C-11), 139.7 (C-12 or C-
14), 139.6 (C-12 or C-14), 128.4 (C-16), 127.3 (C-15), 126.9 (C-
17), 61.1 (C-6), 57.2 (C-10), 54.5 (C-13), 44.8 (C-7), 31.8 (C-3),
29.6 (C-9), 29.1 (C-5), 25.8 (C-4), 22.7 (C-8), 22.6 (C-2), 14.0 (C-
1).
NOE enhancement observed between H-5 and H-9 (4.1%).
HRMS (ESI): m/z [M + Na]+ calcd for C18H24N6: 347.1955; found:
347.1951.
Significant NOE enhancement observed between H-6 and H-10 in
NOESY spectrum.
HRMS (ESI): m/z [M + H]+ calcd for C19H26N6: 339.2297; found:
(Z,6R,10aS)-5-Cyclohexylimino-6-iso-butyl-8,9,10,10a-tetra-
hydro-6H-tetrazolo[1,5-a]pyrrolo[2,1-c]pyrazine (24); Major
Isomer
White crystalline solid; mp 115–118 °C; Rf 0.09 (PE–EtOAc, 5:1);
339.2288.
[a]D25 +125.4 (c 1.0, CHCl3).
(Z,6R,10aS)-5-Benzylimino-6-cyclohexyl-8,9,10,10a-tetrahy-
dro-6H-tetrazolo[1,5-a]pyrrolo[2,1-c]pyrazine (27); Major
Isomer
IR (film): 2965, 1657 (C=N), 1606 cm–1.
1H NMR (600 MHz, CDCl3): d = 4.73 (1 H, dd, J = 8.3, 2.4 Hz, H-
9), 4.59–4.52 (1 H, m, H-12), 3.74 (1 H, dd, J = 8.6, 5.1 Hz, H-5),
2.97 (1 H, app dt, J = 3.7, 8.7 Hz, Ha-6), 2.56–2.48 (1 H, m, Ha-8),
2.34–2.25 (2 H, m, Hb-6 and Hb-8), 1.97–1.84 (4 H, m, H-3, Ha-4,
Ha-7 and Ha-18), 1.84–1.58 (6 H, m, Hb-4, Hb-7, Ha-14, Ha-15, Ha-
16 and Ha-17), 1.57–1.45 (3 H, m, Hb-14, Hb-15 and Hb-18), 1.41–
1.25 (2 H, m, Hb-16 and Hb-17), 0.97 (3 H, d, J = 6.2 Hz, H3-1), 0.93
(3 H, d, J = 6.0 Hz, H3-2).
13C NMR (150 MHz, CDCl3): d = 156.3 (C-10), 136.5 (C-11), 58.7
(C-5), 58.0 (C-12), 57.0 (C-9), 44.3 (C-6), 37.8 (C-4), 34.3 (C-14),
33.1 (C-18), 29.9 (C-8), 25.6 (C-17), 24.7 (C-3), 24.1 (C-15), 24.0
(C-16), 23.2 (C-1), 22.9 (C-7), 22.0 (C-2).
White crystalline solid; mp 131–133 °C; Rf 0.32 (PE–EtOAc, 2:1);
[a]D25 +158.6 (c 1.04, CHCl3).
IR (film): 2932, 2847, 1697 (C=N), 1605 cm–1.
1H NMR (600 MHz, CDCl3): d = 7.45 (2 H, d, J = 7.6 Hz, 2 × H-
16), 7.36 (2 H, app t, J = 7.6 Hz, 2 × H-17), 7.27 (1 H, t, J = 7.4 Hz),
5.35 (1 H, d, J = 17.8 Hz, Ha-14), 5.15 (1 H, d, J = 17.8 Hz, Hb-14),
4.77 (1 H, dd, J = 8.8, 2.4 Hz, H-11), 3.42 (1 H, d, J = 9.4 Hz, H-7),
2.93 (1 H, app dt, J = 4.8, 8.7 Hz, Ha-8), 2.54–2.46 (1 H, m, Ha-10),
2.38 (1 H, d, J = 11.5 Hz, Ha-4), 2.31 (1 H, app q, J = 8.6 Hz, Hb-8),
2.25–2.18 (1 H, m, Hb-10), 2.09–2.02 (1 H, m, H-6), 1.96 (1 H, d,
J = 13.1 Hz, Ha-5), 1.93–1.86 (1 H, m, Ha-9), 1.83–1.76 (1 H, m,
Ha-3), 1.76–1.59 (3 H, m, Ha-1, Ha-2 and Hb-9), 1.42–1.28 (2 H, m,
Hb-2 and Hb-3), 1.27–1.11 (2 H, m, Hb-1 and Hb-5), 1.03–0.94 (1 H,
m, Hb-4).
NOE enhancement observed between H-5 and H-9 (4.7%).
HRMS (ESI): m/z [M + H]+ calcd for C17H28N6: 317.2454; found:
317.2442.
13C NMR (150 MHz, CDCl3): d = 156.8 (C-12), 139.5 (C-15), 138.8
(C-13), 128.4 (C-17), 127.2 (C-16), 126.8 (C-18), 65.6 (C-7), 57.4
(C-11), 54.2 (C-14), 44.6 (C-8), 36.6 (C-6), 31.9 (C-4), 29.7 (C-10),
29.3 (C-5), 26.6 (C-1), 26.2 (C-3), 25.8 (C-2), 23.3 (C-9).
(E,6S,10aS)-5-tert-Butylimino-6-iso-butyl-8,9,10,10a-tetrahy-
dro-6H-tetrazolo[1,5-a]pyrrolo[2,1-c]pyrazine (25)
White crystalline solid; mp 115–117 °C; product decomposes on
silica; [a]D25 +81.3 (c 1.8, CHCl3).
NOE enhancement observed between H-7 and H-11 (4.6%).
HRMS (ESI): m/z [M + H]+ calcd for C20H26N6: 351.2297; found:
351.2289.
IR (film): 2968, 2950, 2868, 2791, 1688 (C=N), 1502 cm–1.
1H NMR (600 MHz, DMSO-d6): d = 4.76 (1 H, dd, J = 8.5, 1.9 Hz,
H-9), 4.33 (1 H, d, J = 4.3 Hz, H-5), 3.11 (1 H, app dt, J = 2.2, 8.9
Hz, Ha-6), 2.46–2.38 (1 H, m, Ha-8), 2.31 (1 H, app q, J = 8.6 Hz,
Hb-6), 2.10–2.03 (1 H, m, Hb-8), 1.95–1.87 (1 H, m, H-3), 1.84–
1.75 (1 H, m, Ha-7), 1.70–1.63 (1 H, m, Hb-7), 1.52 (1 H, app dt,
J = 2.4, 14.4 Hz, Ha-4), 1.38 (9 H, s, 3 × H3-13), 1.27–1.23 (1 H, m,
Hb-4), 0.93 (3 H, d, J = 6.4 Hz, H3-1), 0.88 (3 H, d, J = 6.8 Hz, H3-
2).
13C NMR (150 MHz, DMSO-d6): d = 155.3 (C-10), 145.9 (C-11),
55.9 (C-5), 50.9 (C-6), 50.0 (C-9), 38.6 (C-4), 31.2 (C-13), 29.6 (C-
8), 24.5 (C-3), 23.7 (C-1), 22.9 (C-7), 21.2 (C-2), C-12 signal not
observed.
(Z,6R,10aS)-5-Benzylimino-6-cyclopropyl-8,9,10,10a-tetrahy-
dro-6H-tetrazolo[1,5-a]pyrrolo[2,1-c]pyrazine (28); Major
Isomer
25
Sticky dark-yellow oil; Rf 0.25 (PE–EtOAc, 1:1); [a]D +77.8 (c
0.93, CHCl3).
IR (film): 2972, 1670 (C=N), 1606 cm–1.
1H NMR (600 MHz, CDCl3): d = 7.50 (2 H, d, J = 7.5 Hz, 2 × H-
13), 7.35 (2 H, app t, J = 7.5 Hz, 2 × H-14), 7.25 (1 H, t, J = 7.6 Hz,
H-15), 5.37 (1 H, d, J = 18.3 Hz, Ha-11), 5.28 (1 H, d, J = 18.4 Hz,
Hb-11), 4.48 (1 H, dd, J = 8.0, 3.9 Hz, H-8), 3.15–3.09 (1 H, m, Ha-
5), 2.94 (1 H, d, J = 9.1 Hz, H-4), 2.66 (1 H, dd, J = 16.0, 8.5 Hz,
Hb-5), 2.60–2.51 (1 H, m, Ha-7), 2.32–2.24 (1 H, m, Hb-7), 2.04–
1.94 (1 H, m, Ha-6), 1.83–1.74 (1 H, m, Hb-6), 1.37–1.29 (1 H, m,
H-3), 0.96–0.88 (1 H, m, Ha-1), 0.73–0.66 (1 H, m, Ha-2), 0.53–
0.47 (1 H, m, Hb-2), 0.46–0.39 (1 H, m, Hb-1).
13C NMR (150 MHz, CDCl3): d = 155.7 (C-9), 139.8 (C-12), 139.0
(C-10), 128.3 (C-14), 127.1 (C-13), 126.7 (C-15), 67.4 (C-4), 57.0
(C-8), 54.5 (C-11), 46.6 (C-5), 29.3 (C-7), 22.7 (C-6), 11.7 (C-3),
5.9 (C-1), 3.2 (C-2).
No NOE enhancement observed between H-5 and H-9.
HRMS (ESI): m/z [M + H]+ calcd for C15H26N6: 291.2297; found:
291.2305.
(Z,6R,10aS)-5-Benzylimino-6-pentyl-8,9,10,10a-tetrahydro-6H-
tetrazolo[1,5-a]pyrrolo[2,1-c]pyrazine (26); Major Isomer
25
Orange oil; Rf 0.47 (PE–EtOAc, 1:1); [a]D +106.5 (c 0.35,
CHCl3).
IR (film): 2954, 2927, 1699 (C=N), 1606 cm–1.
1H NMR (600 MHz, CDCl3): d = 7.47 (2 H, d, J =7.6 Hz, 2 × H-15),
3.69 (2 H, app t, J = 7.5 Hz, 2 × H-16), 7.28 (1 H, t, J = 7.3 Hz, H-
NOE enhancement observed between H-4 and H-8 (4.5%).
Synthesis 2006, No. 19, 3215–3223 © Thieme Stuttgart · New York

3222
V. Franckevičius et al.
PAPER
HRMS (ESI): m/z [M + H]+ calcd for C17H20N6: 309.1828; found:
309.1835.
References
(1) (a) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown,
S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123.
(b) Weber, L.; Illgen, K.; Almstetter, M. Synlett 1999, 366.
(c) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471.
(d) Zhu, J. Eur. J. Org. Chem. 2003, 1133. (e) Ramón, D.
J.; Yus, M. Angew. Chem. Int. Ed. 2005, 44, 1602.
(2) Bienaymé, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem.
Eur. J. 2000, 6, 3321.
(Z,6S,10aS)-5-Benzylimino-6-benzyloxymethyl-8,9,10,10a-
tetrahydro-6H-tetrazolo[1,5-a]pyrrolo[2,1-c]pyrazine (29);
Major Isomer
Brown oil; Rf 0.31 (PE–EtOAc, 1:1); [a]D25 +72.8 (c 1.53, CHCl3).
IR (film): 2973, 1699 (C=N), 1606 cm–1.
1H NMR (600 MHz, CDCl3): d = 7.43–7.25 (10 H, m, H-1, 2 × H-
2, 2 × H-3, 3 × H-16, 2 × H-17 and H-18), 5.31 (1 H, d, J = 18.2 Hz,
Ha-14), 5.26 (1 H, d, J = 17.9 Hz, Hb-14), 4.67 (1 H, d, J = 12.3 Hz,
Ha-5), 4.65 (1 H, d, J = 12.3 Hz, Hb-5), 4.58 (1 H, dd, J = 7.9, 3.7
Hz, H-11), 4.21 (1 H, dd, J = 10.4, 4.1 Hz, Ha-6), 4.11–4.06 (1 H,
m, H-7), 3.93 (1 H, dd, J = 10.4, 7.4 Hz, Hb-6), 2.98 (1 H, app dt,
J = 4.6, 8.7 Hz, Ha-8), 2.62–2.50 (2 H, m, Hb-8 and Ha-10), 2.39–
2.31 (1 H, m, Hb-10), 2.05–1.96 (1 H, m, Ha-9), 1.84–1.76 (1 H, m,
Hb-9).
(3) Trost, B. M. Acc. Chem. Res. 2002, 35, 695.
(4) (a) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168. (b) Dömling, A. Curr. Opin. Chem. Biol. 2000, 4,
318. (c) Dömling, A. Curr. Opin. Chem. Biol. 2002, 6, 306.
(d) Ugi, I.; Werner, B.; Dömling, A. Molecules 2003, 8, 53.
(e) Dömling, A. Chem. Rev. 2006, 106, 17.
(5) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbrückner, C. Angew.
Chem. 1959, 71, 386.
(6) (a) Strocker, A. M.; Keating, T. A.; Tempest, P. A.;
Armstrong, R. W. Tetrahedron Lett. 1996, 37, 1149.
(b) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc.
1996, 118, 2574. (c) Keating, T. A.; Armstrong, R. W. J.
Am. Chem. Soc. 1995, 117, 7842. (d) Mjalli, A. M. M.;
Sarshar, S.; Baiga, T. J. Tetrahedron Lett. 1996, 37, 2943.
(e) Hulme, C.; Morrissette, M. M.; Volz, F. A.; Burns, C. J.
Tetrahedron Lett. 1998, 39, 1113. (f) Keating, T. A.;
Armstrong, R. W. J. Org. Chem. 1996, 61, 8935.
(g) Rossen, K.; Sager, J.; DiMichele, L. M. Tetrahedron
Lett. 1997, 38, 3183. (h) Ugi, I.; Rosendahl, F. K.;
Bodesheim, F. Justus Liebigs Ann. Chem. 1963, 666, 54.
(i) Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8.
(j) Kalinski, C.; Umkehrer, M.; Gonnard, S.; Jäger, N.; Ross,
G.; Hiller, W. Tetrahedron Lett. 2006, 47, 2041. (k) Ugi, I.
Angew. Chem., Int. Ed. Engl. 1982, 21, 810. (l) Nixey, T.;
Kelly, M.; Hulme, K. Tetrahedron Lett. 2000, 41, 8729.
(m) Bienaymé, H.; Bouzid, K. Tetrahedron Lett. 1998, 39,
2735. (n) Bossio, R.; Marcos, C. F.; Marcaccini, S.; Pepino,
R. Tetrahedron Lett. 1997, 38, 2519.
(7) For use of a-amino acids, see: (a) Ugi, I.; Demharter, A.;
Hörl, W.; Schmid, T. Tetrahedron 1996, 52, 11657.
(b) Ugi, I.; Hörl, W.; Hanusch-Kompa, C.; Schmid, T.;
Herdtweck, E. Heterocycles 1998, 47, 965. (c) Demharter,
A.; Hörl, W.; Herdtweck, E.; Ugi, I. Angew. Chem., Int. Ed.
Engl. 1996, 35, 173. (d) Park, S. J.; Keum, G.; Kang, S. B.;
Koh, H. Y.; Kim, Y.; Lee, D. H. Tetrahedron Lett. 1998, 39,
7109. (e) Zimmer, R.; Ziemer, A.; Gruner, M.; Brüdgam, I.;
Hartl, H.; Reissig, H.-U. Synthesis 2001, 1649. (f) Kim, Y.
B.; Choi, E. H.; Keum, G.; Kang, S. B.; Lee, D. H.; Koh, H.
Y.; Kim, Y. Org. Lett. 2001, 3, 4149. (g) Godet, T.; Bonvin,
Y.; Vincent, G.; Merle, D.; Thozet, A.; Ciufolini, M. A. Org.
Lett. 2004, 6, 3281.
13C NMR (150 MHz, CDCl3): d = 155.5 (C-12), 139.3 (C-15), 137.7
(C-4), 137.3 (C-13), 128.4, 128.4, 127.9, 127.8, 127.3, 126.9 (C-1,
C-2, C-3, C-16, C-17 and C-18), 73.6 (C-5), 67.6 (C-6), 61.3 (C-7),
57.3 (C-11), 54.6 (C-14), 45.9 (C-8), 28.9 (C-10), 22.5 (C-9).
NOE enhancement observed between H-7 and H-11 (5.1%).
HRMS (ESI): m/z [M + Na]+ calcd for C22H24N6O: 411.1909;
found: 411.1920.
(E,3SR,7aRS)-(1-Benzyl-tetrahydro-3-iso-butyl-1H-pyrro-
lo[1,2-a]imidazol-2(3H)-ylideneamino)formonitrile (30)10,11
White crystalline solid; mp 77–79 °C; Rf 0.28 (PE–EtOAc, 1:1).
IR (film): 2956, 2179 (C≡N), 1607 (C=N) cm–1.
1H NMR (600 MHz, CDCl3): d = 7.36–7.28 (3 H, m, 2 × H-15 and
H-16), 7.22 (2 H, d, J = 7.0 Hz, 2 × H-14), 4.88 (1 H, d, J = 14.8 Hz,
Ha-12), 4.76–4.72 (1 H, m, H-9), 4.14 (1 H, d, J = 14.8 Hz, Hb-12),
3.97 (1 H, app d, J = 10.1 Hz, H-5), 3.19–3.13 (1 H, m, Ha-6), 2.57
(1 H, dd, J = 15.7, 10.0 Hz, Hb-6), 2.03–1.95 (1 H, m, Ha-8), 1.93–
1.87 (1 H, m, H-3), 1.86–1.72 (4 H, m, Ha-4, H2-7 and Hb-8), 1.37–
1.29 (1 H, m, Hb-4), 1.01 (3 H, d, J = 6.6 Hz, H3-1), 0.95 (3 H, d,
J = 6.7 Hz, H3-2).
13C NMR (150 MHz, CDCl3): d = 176.0 (C-11), 134.5 (C-13), 129.0
(C-15), 128.2 (C-16), 128.0 (C-14), 117.5 (C-10), 82.0 (C-9), 68.0
(C-5), 55.4 (C-6), 45.9 (C-12), 39.8 (C-4), 28.7 (C-8), 25.3 (C-3),
23.8 (C-7), 23.4 (C-1), 20.8 (C-2).
No NOE enhancement observed between H-5 and H-9.
HRMS (ESI): m/z [M + H]+ calcd for C18H24N4: 297.2079; found:
297.2078.
Acknowledgment
(8) For use of b-amino acids, see: (a)Pitlik, J.; Townsend, C. A.
Bioorg. Med. Chem. Lett. 1997, 7, 3129. (b) Gedey, S.; Van
der Eycken, J.; Fülöp, F. Org. Lett. 2002, 4, 1967.
(9) Belinke, D.; Taube, R.; Illgen, K.; Nerdinger, S.; Herdtweck,
E. Synlett 2004, 688.
(10) In addition to the two usual isomers, reaction in methanol
(Table 2, entry 1) also afforded a racemic tetrazole
decomposition product 30 (Figure 6), identity of which was
confirmed by full characterisation, including an X-ray
crystal structure (see reference 11).
We thank the EPSRC (V.F., D.A.L., R.M.T.), the Cambridge Euro-
pean Trust (V.F.), Trinity College (D.A.L.) and Novartis (S.V.L.)
for financial support. We also thank Dr J. E. Davies for determining
the crystal structures of 20, 25 and 30, and the EPSRC for financial
assistance towards the purchase of the Nonius CCD diffractometer.
In addition, we thank V. Aureggi and Dr G. Sedelmeier at Novartis
Pharma AG, Werk Klybeck, Postfach CH-4002 Basel, Switzerland,
for the generous gift of (R)-5-pyrrolidin-2-yl-1H-tetrazole.
Synthesis 2006, No. 19, 3215–3223 © Thieme Stuttgart · New York

PAPER
New Heterocyclic Frameworks Generated by an Ugi-Type Multicomponent Reaction
3223
(11) Crystallographic data (excluding structure factors) for the
structures 20, 25 and 30 have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication nos. CCDC-612544, CCDC-612545 and CCDC-
612546, respectively. Copies of the data can be obtained free
of charge on application to the CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK. [Fax: +44(1223)336033; E-mail:
deposit@ccdc.cam.ac.uk].
(12) Franckevičius, V.; Rahbek Knudsen, K.; Ladlow, M.;
Longbottom, D. A.; Ley, S. V. Synlett 2006, 889.
Figure 6 Decomposition product 30
Synthesis 2006, No. 19, 3215–3223 © Thieme Stuttgart · New York