Regioselective Synthesis of 7,8-Dihydropyrrolo[1,2- a ]pyrimidin-4(6 H)-ones and 7,8-Dihydropyrrolo[1,2- a ]pyrimidin-2(6 H)-ones

Article abstract of DOI:10.1055/s-0029-1218566

Annulated analogues of 5,6-dihydroxypyrimidine-4-carboxylate ester and 5,6-dihydroxypyrimidine-4-carboxylamide were synthesized. The intermediary homoallylic amines were subjected to a ring-closure reaction under different reaction conditions. A notable pH-dependency of the ring closure leading to regioisomeric tetrahydropyrrolo[1,2-a]pyrimidines was observed. Treatment with dimethyldioxirane and base led to 3-hydroxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidines while m-chloroperbenzoic acid or NBS afforded 3-hydroxy-2-oxo-2,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidines.

Full text of DOI:10.1055/s-0029-1218566

LETTER
235
Regioselective Synthesis of 7,8-Dihydropyrrolo[1,2-a]pyrimidin-4(6H)-ones
and 7,8-Dihydropyrrolo[1,2-a]pyrimidin-2(6H)-ones
S
ynthesis of 7,8-Dihyd
o
ropyrrolo[1,
n
a
]pyrimidi
i
n-4(6
H
c
)-ones a Donghi,* Silvia Pesci, Vincenzo Summa, Uwe Koch, Stephane Spieser, Cristina Gardelli
Department of Medicinal Chemistry, IRBM-MRL Rome, Via Pontina Km 30,600, 00040 Pomezia, Rome, Italy
Fax +39(06)91093225; E-mail: monica_donghi@merck.com
Received 28 July 2009
reacted with 1,3-dioxo compounds 4 (Scheme 1)6a gener-
ating without any pronounced selectivity both core scaf-
folds 5 and 6 as a mixture which then need to be separated
by chromatography or crystallization.
Abstract: Annulated analogues of 5,6-dihydroxypyrimidine-4-car-
boxylate ester and 5,6-dihydroxypyrimidine-4-carboxylamide were
synthesized. The intermediary homoallylic amines were subjected
to a ring-closure reaction under different reaction conditions. A no-
table pH-dependency of the ring closure leading to regioisomeric
tetrahydropyrrolo[1,2-a]pyrimidines was observed. Treatment with
dimethyldioxirane and base led to 3-hydroxy-4-oxo-4,6,7,8-tet-
rahydropyrrolo[1,2-a]pyrimidines while m-chloroperbenzoic acid
or NBS afforded 3-hydroxy-2-oxo-2,6,7,8-tetrahydropyrrolo[1,2-
a]pyrimidines.
O
O
+
EtO
OEt
OEt
R
NH2
N
3
4
R = H, Me
EtOH
Δ
Key words: antiviral agents, bicyclic compounds, heterocycles,
regioselectivity, ring closure
O
O
R
The development of potent and effective antiviral drugs
for the treatment of viral diseases like those caused by the
human immunodeficiency virus (HIV) or by the flavivi-
ridae viruses (e.g., the hepatitis C virus) is an important
goal in drug research.
N
N
+
N
R
N
5
ca. 1:3
6
In this context our group focused its work on dihydroxy-
pyrimidines and N-Me-pyrimidones. Their attractive in-
hibitory activity is derived from binding to the active
site.1,2 This class of heterocycles can be prepared with a
wide variety of substitution patterns.3
Scheme
1
Preparation of 7,8-dihydropyrrolo[1,2-a]pyrimidin-
4(6H)-ones 5 and 7,8-dihydropyrrolo[1,2-a]pyrimidin-2(6H)-ones 6
O
Br–
+HN
DCE
OH
Br
R
Monosubstituted bicyclic analogues of class 1 (Figure 1),
for example, the 7,8-dihydropyrrolo[1,2-a]pyrimidin-
4(6H)-ones (n = 1)4a–4g have recently attracted atten-
tion;5a,b but little is known about compounds of class 2, for
example, the 7,8-dihydropyrrolo[1,2-a]pyrimidin-2(6H)-
ones (n = 1).6a,b
+
O
NH2
R = H; 5-Cl, 3-OMe,
6-Me, 4-F, 4,5-Ph2
Et3N
O
HN
R
O
O
Br
N
N
OH
N
n
R = H, NR1R2
MeCN
Δ
N
n = 1, 2
N
n
O
R
1
2
N
O
HO
Figure 1 7,8-Dihydropyrrolo[1,2-a]pyrimidin-4(6H)-one (1, n = 1)
and 7,8-dihydropyrrolo[1,2-a]pyrimidin-2(6H)-one (2, n = 1)
N
N
+
R
R
N
HO
depending on R: from 1:4 to 2:1
7
8
Up to now, no protocol leading exclusively to scaffold 2
has been described. The classical approach to this class
employs 3,4-dihydro-2H-pyrrol-5-amines 3 which are
Scheme 2 Preparation of tetrahydro[2,1-b]quinazolin-11-ones 7
and tetrahydro[1,2-a]quinazolin-6-ones 8
Another annulation protocol leading to tetrahydro[2,1-
b]quinazolin-11-ones 7 and tetrahydro[1,2-a]quinazolin-
6-ones 8 via a cyclization of a 2-substituted 4(3H)-
SYNLETT 2010, No. 2, pp 0235–0239
Advanced online publication: 11.12.2009
DOI: 10.1055/s-0029-1218566; Art ID: D20009ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
0

236
M. Donghi et al.
LETTER
quinazolinone has been described7 (Scheme 2), though
also in this case no selectivity in the cyclization reaction
was observed.
NHBoc
CO2H
However, to the best of our knowledge no preparation of
annulated methyl 5,6-dihydroxypyrimidine carboxylates
such as 9a (Figure 2) belonging to class 2 is described.
R
R
NBoc
N
NBoc
CN
In the course of our research in the antiviral field we were
interested in the synthesis of disubstituted derivatives of
annulated methyl 5,6-dihydroxypyrimidine carboxylates
such as 9b which so far are not preceded in literature
(Figure 2).
NH2OH, IPA
91%
DMAD, MeOH
NH2
OH
11 R = H
12 R = Me
13 R = H
14 R = Me
OH
N
O
N
1. xylene, 140 °C
2. Bz2O, CH2Cl2, py
OBz
OMe
CO2Me
N
R
O
Y
CO2Me
NH2
O
37%
OH
N
OH
NBoc
BocN
O
N
OMe
R
N
X
15 R = H
16 R = Me
OMe
17 R = H
18 R = Me
N
O
X
O
9a
9b
Scheme 3 Preparation of intermediate pyrimidines 17 and 18
Y
Figure 2 Annulated methyl 5,6-dihydroxypyrimidine carboxylates
O
OH
OBz
To achieve the annulation we envisaged a ring-closing
protocol based on epoxide 10 (Figure 3). From our expe-
rience it might have been opened in basic media from the
N1 nitrogen of the pyrimidine2d and give after a favored
5-exo ring closure the desired compound 9, even though
other systems in literature show a nonselective or even a
preference for N3-alkylation.8
N
m-CPBA,
CH2Cl2
OBz
OMe
Boc
HN
N
OMe
N
46%
N
O
NHBoc
O
HO
17
19a (cis)
19b (trans)
O
OH
MeOH, 80 °C
N
19b
Boc
HN
O
OH
N
OBz
N1
O
O
20
OH
3
N
OMe
O
OBz
N
NBS, DMSO
H2O
OBz
OMe
N
Boc
N
O
Me
OMe
Boc
N
N
60%
10
N
R
O
BocN
O
Figure 3 Epoxide intermediate 10
21 R = H
22 R = Me
R
17 R = H
18 R = Me
Br
1. NaN3
To this end the intermediates 17 and 18 were prepared
modifying a procedure described by Culbertson.9 Com-
mercially available allyl glycine was transformed in a few
steps into the corresponding amidoximes 13 and 14 via
the nitriles 11 and 12 using standard methodology
(Scheme 3). The amidoximes 13 and 14 were reacted with
dimethyl acetylenedicarboxylate (DMAD) to afford the
Michael adducts 15 and 16 as a mixture of E/Z-isomers
which underwent a thermal rearrangement to afford 5,6-
dihydroxypyrimidine carboxylate methyl esters.10 Protec-
tion with benzoic anhydride went smoothly to give the de-
sired intermediates 17 and 18.2a,c,11
O
O
N
DMF
2. H2, Pd/C
MeOH
OH
N
OH 4-FC6H4CH2Br
N
N
KH, THF
Boc
Boc
O
O
46%
52%
N
N
N
R
from 18
64%
NH
from 17
25
23 R = H
24 R = Me
F
Scheme 4 N3-Mediated ring closure and further elaboration of the
products
To obtain epoxide 10 we first used the standard conditions
with meta-chloroperbenzoic acid. However, after isola-
tion and thorough 1H NMR and 13C NMR analysis12 of the
material obtained, the cyclized products 19a and 19b (two
expected diastereomers, ratio = 1:2) were preliminarily
identified as the outcome of the reaction, and the desired
epoxide was not isolated (Scheme 4).13
Compound 19b was derivatized to the lactone 20 (com-
pletely characterized by 1H NMR, 13C NMR, and 1H–13C
HMBC experiments) which confirmed unambiguously
the previous structural assignment of 19b as the N3-alky-
lated product.14 The lactone 20 was identified as the trans-
1
isomer by H–1H NOESY experiment, allowing also the
assignment of the relative stereochemistry of 19b. We hy-
Synlett 2010, No. 2, 235–239 © Thieme Stuttgart · New York

LETTER
Synthesis of 7,8-Dihydropyrrolo[1,2-a]pyrimidin-4(6H)-ones
237
pothesized that the impossibility to isolate compound 10 We assume that a change in the protonation state of the
was due to the fact that the ring-opening reaction of the pyrimidine changes the equilibrium. Thus, we expect in
newly generated epoxide occurs faster than its formation. acidic solution the oxo tautomer C, in which N1 cannot
act as a nucleophile, to be favored. In basic solution we
As an alternative, the preparation of a bromohydrin15 was
expect the aromatic tautomer A, which allows maximal
taken into consideration. Therefore, 17 and 18 were treat-
delocalization of the negative charge, to be preferred. In
ed with NBS in DMSO–H2O. This resulted in the direct
this form the sterically more accessible N1 is the most
reactive.
formation of bromides 21 and 22 as a mixture of diastere-
omers (1:1),16 while no bromohydrin was observed. This
can be rationalized by a rapid nucleophilic attack of the
OH
N
OH
N
ring nitrogen N3 on the intermediary bromonium cation,
which occurs faster than the addition of water. By treat-
ment with sodium azide and subsequent catalytic hydro-
genation we were able to convert the bromides 21 and 22
into the novel tricyclic lactams 23 and 24.17 Compound 24
was further alkylated with p-fluorobenzyl bromide to
yield 25 – a new interesting scaffold in the HIV integrase
field. Furthermore, compounds 19, 21, and 22 are suitable
intermediates for elaboration by alkylation, activation, or
nucleophilic displacement. However, while the bromina-
tion leading to intermediates 21 and 22 proceeded cleanly
and in good yield (allowing this material to be employed
as crude in further reactions), the use of m-chloroperben-
zoic acid afforded the hydroxyl derivative 19 in lower
yield and necessitated careful purification.
OBz
OBz
O
O
N
N
acetone
Boc
Me
Boc
Me
O
O
N
N
OMe
OMe
18
O
O
N
10
OBz
OMe
Boc
N
N
Me
O
26
HO
OH
N
OH
O
OBz
1.
N
OBz
OMe
O
O
Boc
Me
N
These two results led us to the conclusion that the acidic
medium could play a major role in the regioselective at-
tack of the ring nitrogen N3 on the epoxide or on the bro-
monium intermediates. To direct the cyclization on the
ring nitrogen N1, we envisaged as a solution the formation
of the epoxide in neutral conditions. Indeed, formation of
the epoxide was detected by using dimethyldioxirane,18
but again this intermediate was unstable and underwent
attack by the ring nitrogen N3, resulting in the formation
of 26 (Scheme 5). However, when the reaction was car-
ried out with dimethyldioxirane in the presence of cesium
carbonate, isolation of the desired product 27 could be
achieved. In accordance with our previous experience in
basic media the more reactive pyrimidine nitrogen is N1.
This gives rise to the formation of the desired 7,8-dihydro-
pyrrolo[1,2-a]pyrimidin-4(6H)-one 27 as a mixture of
diastereomers (1:1).19
acetone
O
N
2. Cs2CO3
50%
N
OMe
N
O
Me
Boc
18
27a (cis)
27b (trans)
Scheme 5 Mild epoxidation conditions to obtain either ring-closing
products 26 and 27
We have been able to show that the ring closure of activat-
ed 2-but-3-en-1-ylpyrimidin-4(3H)-ones 17 and 18 is a
highly pH-dependent process which can be exploited to
give selectively either of the possible products. The annu-
lation reaction proceeds under mild conditions. While N3-
mediated cyclization to 7,8-dihydropyrrolo[1,2-a]pyrimi-
din-2(6H)-ones (e.g., 19, 21, 22, 26) is observed in acidic
to neutral conditions, the N1-derived cyclization to 7,8-
dihydropyrrolo[1,2-a]pyrimidin-4(6H)-ones (e.g., 27) is
obtained under basic conditions. The N3-ring-closure
products could be further elaborated to furnish novel tri-
cyclic compounds (e.g., 20, 23). Our regiocontrolled ap-
proach compares advantageously with previous methods
in that a common intermediate can be used to trigger
either ring closure in a selective manner.
In the course of our work, we frequently observed the oc-
currence of rotamers due to hindered rotation of the Boc-
substituted tertiary amine (e.g., in 22, 24, and 27).
The pyrimidine can adopt three different tautomeric forms
(Figure 4) with the two pyrimidine N-atoms having differ-
ent reactivities in each tautomer.
OH
O
O
References and Notes
OR
O
OR
O
H
R
OR
O
N
N
N
(1) (a) Summa, V.; Petrocchi, A.; Matassa, V. G.; Taliani, M.;
Laufer, R.; De Francesco, R.; Altamura, S.; Pace, P. J. Med.
Chem. 2004, 47, 5336. (b) Koch, U.; Attenni, B.;
OMe
OMe
OMe
R
R
N
N
N
H
B
A
C
Malancona, S.; Colarusso, S.; Conte, I.; Di Filippo, M.;
Harper, S.; Pacini, B.; Giomini, C.; Thomas, S.; Incitti, I.;
Tomei, L.; De Francesco, R.; Altamura, S.; Matassa, V. G.;
Narjes, F. J. Med. Chem. 2006, 49, 1693.
Figure 4 Tautomeric forms of the pyrimidine educt
Synlett 2010, No. 2, 235–239 © Thieme Stuttgart · New York

238
M. Donghi et al.
LETTER
(2) (a) Summa, V.; Petrocchi, A.; Matassa, V. G.; Gardelli, C.;
Muraglia, E.; Rowley, M.; Paz, O. G.; Laufer, R.;
Monteagudo, E.; Pace, P. J. Med. Chem. 2006, 49, 6646.
(b) Petrocchi, A.; Koch, U.; Matassa, V. G.; Pacini, B.;
Stillmock, K. A.; Summa, V. Bioorg. Med. Chem. Lett.
2007, 17, 350. (c) Pace, P.; Di Francesco, M. E.; Gardelli,
C.; Harper, S.; Muraglia, E.; Nizi, E.; Orvieto, F.; Petrocchi,
A.; Poma, M.; Rowley, M.; Scarpelli, R.; Laufer, R.;
Gonzalez Paz, O.; Monteagudo, E.; Bonelli, F.; Hazuda, D.;
Stillmock, K. A.; Summa, V. J. Med. Chem. 2007, 50, 2225.
(d) Gardelli, C.; Nizi, E.; Muraglia, E.; Crescenzi, B.;
Ferrara, M.; Orvieto, F.; Pace, P.; Pescatore, G.; Poma, M.;
Rico Ferreira, M. d. R.; Scarpelli, R.; Homnick, C. F.;
Ikemoto, N.; Alfieri, A.; Verdirame, M.; Bonelli, F.;
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13C NMR data of the major isomer 19b are reported in ref.
13 (refer to Figure 3 for the numbering of the pyrimidine
moiety).
(13) trans-Methyl 3-(Benzoyloxy)-8-[(tert-butoxycarbonyl)-
amino]-6-(hydroxymethyl)-2-oxo-2,6,7,8-tetrahydro-
pyrrolo[1,2-a]pyrimidine-4-carboxylate (19b)
To a solution of methyl 5-(benzoyloxy)-2-({1-[(tert-
butoxycarbonyl)amino]but-3-en-1-yl})-6-hydroxypyrimi-
dine-4-carboxylate (17, 140 mg, 0.32 mmol) in CH2Cl2 (0.1
M), MCPBA (70%, 70 mg, 0.32 mmol) was added, and the
suspension was stirred at r.t. After 1 h another equiv of
MCPBA (70%, 70 mg, 0.32 mmol) was added, and the
reaction mixture was stirred at r.t. for 36 h. Sodium
thiosulfate was added, and the organic phase was separated
and washed with aq NH4HCO3 (sat., 4×). The organic layer
was dried over Na2SO4 and concentrated to dryness under
reduced pressure. The product was purified by preparative
RP-HPLC, and the two diastereomers were separated, using
H2O (0.1% TFA) and MeCN (0.1% TFA) as eluents
(column: C18). The main diastereomer was obtained after
lyophilization of the pooled product fractions (46%).
1H NMR (400 MHz, 300 K, CD3CN): d = 8.12 (d, J = 7.4 Hz,
2 H), 7.73 (t, J = 7.4 Hz, 1 H), 7.57 (t, J = 7.4 Hz, 2 H), 5.76
(d, J = 6.7 Hz, 1 H), 5.05 (m, 1 H), 4.96 (m, 1 H), 3.79 (s, 3
H), 3.72 (dd, J = 12.2, 3.4 Hz, 1 H), 3.63 (m, 1 H), 2.50–2.36
(m, 2 H), 1.43 (s, 9 H). 13C NMR (100 MHz, 300 K,
CD3CN): d = 166.4 (C-6), 165.6 (C-2), 164.4, 161.2, 156.4,
135.9 (C-5), 135.3, 134.3 (C-4), 131.0, 129.9, 129.3, 80.5,
64.4, 62.6, 54.4, 53.6, 31.7, 28.5. MS: m/z = 537 [M + H]+.
(14) trans-tert-Butyl-(5-hydroxyl)-4,6-dioxo-1,2,4,6,8,8a-
hexahydro-7-oxa-3,8b-diazaacenaphthylen-2-yl)
Carbamate (20)
(e) Muraglia, E.; Kinzel O. Gardelli, C.; Crescenzi, B.;
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Monteagudo, E.; Fonsi, M.; Felock, P. J.; Rowley, M.;
Summa, V. J. Med. Chem. 2008, 51, 861.
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A solution of compound 19b (40 mg, 0.09 mmol) in MeOH
(0.02 M) was stirred at 80 °C for 36 h. The solvent was
evaporated under reduced pressure, and the product was
purified by preparative RP-HPLC using H2O (0.1% TFA)
and MeCN (0.1% TFA) as eluents (column: C18). 1H–13C
HMBC experiment performed on 20 showed the key
heteronuclear correlations between OCH2CH and C-2, C-4
of the pyrimidine core, while no correlation to C-6 was
detected (see Figure 3 for the numbering of the pyrimidine
moiety), allowing the regiochemistry of the previous
alkylation step to be assigned at N3. 1H NMR (500 MHz,
300 K, DMSO-d6): d = 10.40 (br s, 1 H), 7.69 (d, J = 7.9 Hz,
1 H), 4.73 (m, 1 H), 4.70 (m, 1 H), 4.66 (m, 1 H), 4.42 (t,
J = 10.9 Hz, 1 H), 2.27 (m, 1 H), 2.07 (m, 1 H), 1.39 (s, 9 H).
13C NMR (100 MHz, 300 K, DMSO-d6): d = 167.6 (C-6),
156.9, 155.9 (C-2), 154.8, 146.3 (C-5), 111.4 (C-4), 78.8,
70.0, 55.5, 53.3, 30.6, 28.1. MS: m/z = 324 [M + H]+.
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8-[(tert-butoxycarbonyl)(methyl)amino] 2-Oxo-2,6,7,8-
tetrahydropyrrolo[1,2-a]pyrimidine-4-carboxylate (22)
To a solution of methyl 5-(benzoyloxy)-2-({1-[(tert-butoxy-
carbonyl)(methyl)amino]but-3-en-1-yl})-6-hydroxypyrimi-
dine-4-carboxylate (18, 650 mg, 1.42 mmol) in DMSO
(0.142 M), H2O (2.84 mmol), and NBS (364 mg, 2.84 mmol)
were added, and the solution was stirred at r.t. After 10 min
H2O was added, the aqueous phase was extracted with
EtOAc, and the combined organic layers were dried over
Na2SO4 and concentrated to dryness under reduced pressure.
The product was purified by preparative RP-HPLC, and the
two diastereomers were separated, using H2O (0.1% TFA)
and MeCN (0.1% TFA) as eluents (column: C18). The
products were obtained after lyophilization of the pooled
product fractions (60%; relative stereochemistry:
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(12) Preliminary assignment of compounds 19 as the N3-
alkylated products was based on the chemical shift of carbon
signals of the pyrimidine core, not being consistent with data
previously obtained from a variety of N1-alkylated
pyrimidones (Pesci, S.; unpublished results); diagnostic
Synlett 2010, No. 2, 235–239 © Thieme Stuttgart · New York

LETTER
Synthesis of 7,8-Dihydropyrrolo[1,2-a]pyrimidin-4(6H)-ones
239
undetermined). 1H–13C HMBC experiments performed on
ra), 1.44 (s, 2.25 H), 1.39 (s, 2.25 H), 1.31–1.28 (br, s, 4.5 H).
13C NMR (100 MHz, 300 K, DMSO-d6): d = 166.6, 161.6,
161.4, 156.0, 155.8, 155.3, 154.9, 154.0, 143.7, 143.6,
115.5, 115.3, 115.1, 79.8, 79.6, 60.1 (rb), 59.9 (rd), 59.7 (rc),
58.1 (ra), 56.7 (rc,rd), 52.8 (ra,rb), 44.1, 43.9, 43.8 (ra),
33.3, 30.7, 30.0 (rb), 29.4 (rc,rd), 28.8 (ra), 27.9. MS: m/z =
337 [M + H]+.
both fractions showed the key heteronuclear correlations
between BrCH2CH and C-2, C-4 of the pyrimidine core (see
Figure 3 for the numbering of the pyrimidine moiety), while
no correlation to C-6 was detected, allowing the regiochemi-
stry of the alkylation to be assigned at N3. Both samples
displayed two sets of broad proton signals at T = 300 K;
exchange between the two rotamers was assessed by VT-1H
NMR.
(18) Adam, W.; Hadjiarapoglu, L.; Smerz, A. Chem. Ber. 1991,
124, 227.
First fraction (mixture of two rotamers, ‘ra’ and ‘rb’;
corresponding relative ratio 3:7): 1H NMR (600 MHz, 294
K, DMSO-d6): d = 8.10–8.06 (m, 2 H), 7.78 (t, J = 7.3 Hz, 1
H), 7.62 (t, J = 7.3 Hz, 2 H), 5.63 (m, 0.3 H, ra), 5.31 (m, 0.7
H, rb), 5.26 (m, 0.3 H, ra), 5.13 (br s, 0.7 H, rb), 3.95–3.87
(m, 1 H), 3.84–3.73 (m, 1 H), 3.82 (s, 2.1 H, rb), 3.81 (s, 0.9
H, ra), 2.95 (s, 2.1 H, rb), 2.79 (s, 0.9 H, ra), 2.68–2.60 (m,
1 H), 2.56 (dd, J = 12.6, 9.4 Hz, 0.7 H, rb), 2.43 (dd,
J = 12.7, 9.1 Hz, 0.3 H, ra), 1.42 (s, 2.7 H, rb), 1.26 (s, 6.3 H,
ra). 13C NMR (100 MHz, 294 K, DMSO-d6): d = 164.3 (ra
and rb, C-6), 164.2 (rb, C-2), 163.2 (ra, C-2), 162.8 (rb),
162.7 (ra), 159.6, 154.8 (ra), 153.6 (rb), 135.1 (ra, C-5),
134.9 (rb, C-5), 134.5, 131.5 (ra, C-4), 131.4 (rb, C-4),
129.9, 129.2, 127.7 (ra), 127.6 (rb), 79.8, 60.5 (ra), 60.2 (rb),
59.8 (rb), 57.8 (ra), 54.3 (ra), 54.1 (rb), 36.2 (rb), 35.8, 32.3
(ra), 30.9 (rb), 29.0 (ra), 27.9 (ra), 27.6 (rb). MS: m/z = 537
[M + H]+.
(19) cis- and trans-Methyl 3-(Benzoyloxy)-8-[(tert-butoxy-
carbonyl)(methyl)amino]-6-(hydroxymethyl)-4-oxo-
4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-2-carboxy-
late (27a and 27b)
To a solution of methyl 5-(benzoyloxy)-2-({1-[(tert-butoxy-
carbonyl)(methyl)amino]but-3-en-1-yl})-6-hydroxypyrimi-
dine-4-carboxylate (18, 0.44 mmol) was added dimethyldi-
oxirane (freshly prepared, solution in acetone, 6 mL), and
the solution was stirred at r.t. in the dark. After 4 h Cs2CO3
(1.29 mmol) was added, and the reaction mixture was stirred
at r.t. for 2 h. Then the solvent was evaporated, EtOAc was
added, and the organic layer was washed with H2O, dried
over Na2SO4, and concentrated to dryness under reduced
pressure. The product was purified by preparative RP-
HPLC, and the two diastereomers were separated using H2O
(0.1% TFA) and MeCN (0.1% TFA) as eluents (column:
C18). The products were obtained after lyophilization of the
pooled product fractions (50%). 1H–13C HMBC experiments
performed on 27 showed on both diastereomers the key
heteronuclear correlations between HOCH2CH and C-2, C-
6 of the pyrimidine core (see Figure 3 for the numbering of
the pyrimidine moiety), while no correlation to C-4 was
detected, allowing the regiochemistry of the alkylation to be
assigned at N1. Determination of the relative
Second fraction: 1H NMR (500 MHz, 325 K, DMSO-d6):
d = 8.07 (m, 2 H), 7.77 (t, J = 7.3 Hz, 1 H), 7.62 (t, J = 7.3
Hz, 2 H), 5.53 (t, J = 9.7 Hz, 1 H), 5.03 (m, 1 H), 3.88 (s, 3
H), 3.82 (dd, J = 11.7, 1.8 Hz, 1 H), 3.68 (m, 1 H), 2.84 (s, 3
H), 2.83 (m, 1 H), 2.10 (m, 1 H), 1.43 (s, 9 H). 13C NMR (100
MHz, 325 K, DMSO-d6): d = 163.5 (C-6), 162.7 (C-2),
162.5, 159.2, 154.6, 134.3 (C-5), 134.1, 131.3 (C-4), 129.6,
128.8, 127.5, 79.7, 59.4, 57.1, 53.9, 35.4, 31.4, 28.5, 27.7.
MS: m/z = 537 [M + H]+.
stereochemistry (‘cis’, ‘trans’) and assessment of the
exchange between the two sets of signals observed for each
stereoisomer were performed combining results from 1H–1H
NOESY and ROESY experiments at different temperatures.
‘trans’-Isomer (mixture of two rotamers ra,rb;
(17) cis- and trans-tert-Butyl-(5-hydroxy)-4,6-dioxo-
2,4,6,7,8,8a-hexahydro-1H-3,7,8b-triazaacenaphthylen-
2-yl) methyl carbamate (24)
To a solution of compound 22 (mixture of diastereomers,
crude material; 761 mg, 1.42 mmol) in DMF (0.5 M) NaN3
(185 mg, 2.84 mmol) was added, and the solution was stirred
at r.t. After 48 h the solution was concentrated to dryness
under reduced pressure. To the residue in MeOH (0.142 M)
was added Pd/C (10%, 80 mg), and the reaction mixture was
stirred at r.t. After 16 h the suspension was filtered over
Celite, and the filtrate was concentrated to dryness under
reduced pressure. The product was purified by preparative
RP-HPLC, using a gradient of H2O (0.1% TFA) and MeCN
(0.1% TFA) as eluents (column: C18). The product was
obtained after lyophilization of the pooled product fractions
(46% over three steps). Four sets of NMR signals were
detectable, corresponding to the two (1:1) diastereomers
‘cis’/‘trans’ (each one as a mixture of rotamers, indicated as
‘ra,rb’ for the ‘cis’-isomer, ‘rc,rd’ for the ‘trans’-isomer).
Determination of the relative stereochemistry (‘cis’, ‘trans’)
and assessment of the exchange between the two sets of
signals from each stereoisomer were performed combining
results from 1H–1H NOESY and ROESY experiments at
different temperatures.
corresponding relative ratio = 7:3): 1H NMR (600 MHz, 294
K, DMSO-d6): d = 8.80 (d, J = 7.3 Hz, 2 H), 7.79 (t, J = 7.3
Hz, 1 H), 7.63 (t, J = 7.3 Hz, 2 H), 5.72 (t, J = 8.9 Hz, 0.3 H),
5.09 (br s, 0.7 H), 4.71 (d, J = 9.5 Hz, 0.7 H), 4.68 (d, J = 9.5
Hz, 0.3 H), 3.91–3.85 (m, 1 H), 3.75 (s, 2.1 H), 3.74 (s, 0.9
H), 3.61 (d, J = 11.4 Hz, 0.3 H), 3.58 (d, J = 11.4 Hz, 0.7 H),
2.95 (s, 2.1 H), 2.76 (s, 0.9 H), 2.60–2.44 (m, 1.4 H), 2.51–
2.34 (m, 0.6 H), 1.44 (s, 0.9 H), 1.24 (s, 2.1 H). 13C NMR
(100 MHz, 294 K, DMSO-d6): d = 163.2, 162.9, 161.7 (ra,
C-2), 160.5 (rb, C-2), 155.8 (ra and rb, C-6), 154.9 (rb),
153.7 (ra), 143.4 (ra, C-4), 142.9 (rb, C-4), 136.6 (rb, C-5),
136.1 (ra, C-5), 134.6, 129.9, 129.2, 127.7, 79.8 (rb), 79.7
(ra), 61.4 (ra), 60.2, 59.4, 59.1 (rb), 52.9, 35.5 (ra), 31.5 (rb),
29.7 (ra), 28.0(rb), 27.6 (ra,rb). MS: m/z = 474 [M + H]+.
‘cis’-Isomer (mixture of two rotamers ra,rb; corresponding
relative ratio = 1:1): 1H NMR (600 MHz, 294 K, DMSO-d6):
d = 8.08 (d, J = 7.3 Hz, 2 H), 7.78 (t, J = 7.3 Hz, 1 H), 7.63
(t, J = 7.3 Hz, 2 H), 5.63 (t, J = 8.8 Hz, 0.5 H, ra), 5.27 (s, br,
0.5 H, rb), 4.52 (s, br, 0.5 H, ra) 4.47 (s, br, 0.5 H, rb), 4.23
(d, J = 10.1 Hz, 0.5 H, ra), 4.12 (m, 0.5 H, rb), 3.76 (m, 0.5
H, rb), 3.74 (s, 3 H), 3.59 (d, J = 10.1 Hz, 0.5 H, ra), 2.80 (s,
1.5 H, rb), 2.76 (s, 1.5 H, ra), 2.61 (m, 0.5 H, rb), 2.55 (m,
0.5 H, ra), 2.22 (m, 0.5 H, rb), 2.18 (m, 0.5 H, ra), 1.45 (s,
4.5 H, ra,rb), 1.34 (s, 4.5 H, rb,ra). 13C NMR (100 MHz, 294
K, DMSO-d6): d = 163.1, 163.0, 160.8 (rb, C-2), 160.4 (ra,
C-2), 156.8 (ra), 156.6 (rb), 155.0 (ra, C-6), 154.2 (rb, C-6),
142.6 (ra and rb, C-4), 136.7 (ra, C-5), 136.4 (rb, C-5),
134.6, 129.9, 129.2, 127.7, 79.8, 60.4 (rb), 60.2 (ra), 58.9
(rb), 58.7 (rb), 58.5 (ra), 57.0(ra), 52.9, 31.6 (rb), 30.7 (ra),
‘trans’-Isomer 1H NMR (500 MHz, 300 K, DMSO-d6): d =
10.22 (br s, 1 H), 8.75 (br s, 1 H), 5.58 (br t, J = 9.2 Hz, 0.25
H, ra), 5.15 (br s, 0.25 H, rb), 5.09 (br s, 0.25 H, rc), 5.00 (br
s, 0.25 H, rd), 4.62 (br s, 0.50 H, rc,rd), 4.28 (br s, 0.50 H,
ra,rb), 3.70–3.56 (m, 1 H), 3.49 (t, J = 12.2 Hz, 0.25 H, ra),
3.39 (t, J = 11.9 Hz, 0.75 H, rb,rc,rd), 2.82 (s, 0.75 H), 2.80
(s, 1.5 H), 2.70 (s, 1.5 H), 2.70 (s, 0.75 H), 2.66 (m, 0.25 H,
rb), 2.54 (m, 0.25 H, ra), 2.40–2.30 (m, 0.5 H, rc,rd), 2.24–
2.14 (m, 0.5 H, rc,rd), 2.02 (m, 0.25 H, rb), 1.98 (m, 0.25 H,
28.0, 27.0(rb), 25.4 (ra). MS: m/z = 474 [M + H]+
.
Synlett 2010, No. 2, 235–239 © Thieme Stuttgart · New York

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