Selective N1-alkylation of 3,4-dihydropyrimidin-2(1H)-ones using Mitsunobu-type conditions

Article abstract of DOI:10.1055/s-2002-34881

The regioselective N1-alkylation of 3,4-dihydropyrimidin-2(1H)-ones via Mitsunobu reaction is reported. Using the highly reactive Mitsunobu coupling reagent combination N,N,N′,N′-tetramethylazodicarboxamide/tributylphosphine (TMAD-TBP) and a set of primary alcohols a small library of N1-alkylated dihydropyrimidones is obtained in good to excellent yields.

Full text of DOI:10.1055/s-2002-34881

LETTER
1901
Selective N1-Alkylation of 3,4-Dihydropyrimidin-2(1H)-ones Using
Mitsunobu-Type Conditions
Mitsunobu-Type
A
o
lkylation of
r
3,4-Dihy
i
dropyr
s
imidin-2(1
H
)-o
D
s
allinger, C. Oliver Kappe*
Institute of Chemistry, Organic and Bioorganic Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, 8010 Graz, Austria
Fax +43(316)3809840; E-mail: oliver.kappe@uni-graz.at
Received 18 August 2002
Mitsunobu set of reagents diethyl azodicarboxylate–tri-
phenylphosphine (DEAD–TPP) are limited to rather
acidic nucleophiles (N-, O- and C-acidic compounds)
with a pKa<11. For nucleophiles having a pKa>11, more
Abstract: The regioselective N1-alkylation of 3,4-dihydropyrimi-
din-2(1H)-ones via Mitsunobu reaction is reported. Using the high-
ly reactive Mitsunobu coupling reagent combination N,N,N ,N -
tetramethylazodicarboxamide/tributylphosphine
(TMAD–TBP)
and a set of primary alcohols a small library of N1-alkylated dihy- active Mitsunobu coupling reagents, like 1,1 -(azodicar-
dropyrimidones is obtained in good to excellent yields.
bonyl)dipiperidine (ADDP) and N,N,N ,N -tetramethyla-
zodicarboxamide (TMAD), were developed by Tsunoda
and co-workers.9,10 In combination with tributylphosphine
(TBP) these commercially available reagents can be used
for the alkylation of low acidity nucleophiles such as
amides.11
Key words: Mitsunobu reaction, selective alkylations, amides, di-
hydropyrimidones, Biginelli condensation
The multifunctionalized dihydropyrimidine scaffold 1
(DHPMs, ‘Biginelli compounds’) represents a heterocy-
clic system of remarkable pharmacological efficiency.1 A
wide range of biological activities has been ascribed to
these partly reduced pyrimidine derivatives, and a number
of lead compounds based on that structural core have been
developed.2,3 In general, DHPMs are available via Bigi-
nelli three-component condensation employing CH-acid-
ic carbonyl compounds, aldehydes and urea building
blocks.1,4 This one-pot multicomponent reaction generally
works best with urea itself, providing DHPM derivatives
1 in high yields. If N-monosubstituted alkyl ureas are em-
ployed under standard reaction conditions, lower yields
are frequently obtained.4–6 Furthermore, the commercial
availability of substituted ureas is limited, thereby making
the preparation of specific N1-substituted DHPMs often
troublesome. In the context of a combinatorial program
directed toward the synthesis of diverse DHPM libraries,6
we required access to various, specifically substituted,
N1-functionalized DHPM analogs. Since the selective
N1-alkylation of DHPMs using standard alkylation condi-
tions (i.e. alkyl halides in the presence of base) can be
rather unselective and often leads to mixtures of N1/N3-,
or dialkylated products,7 we have considered the use of
Mitsunobu conditions as an alternative to mediate the di-
rect alkylation of DHPMs at the acidic N1-amide func-
tionality with alcohols. Alcohols are usually stable and
easy to handle, can be purchased with a broad variety of
additional functional groups, and are therefore ideal build-
ing blocks for the preparation of compound libraries.
It appeared to us that the presence of the enamine moiety
(O=C–C=C–NH) in the DHPM scaffold 1 would allow
the regioselective alkylation of the N1-position under
Mitsunobu conditions, taking advantage of the increased
acidity of the hydrogen at N1 over N3. Here we report our
results on the regioselective N1-monoalkylation of
DHPMs utilizing Mitsunobu-type chemistry.
We started our investigations by exploring various classi-
cal Mitsunobu alkylation conditions employing DHPM 1
(R1 = EtO, R2 = Ph, R3 = Me) as a model substrate and
methanol as the alkylating agent (R4 = Me). Disappoint-
ingly, all attempts to afford alkylation utilizing the tradi-
tional Mitsunobu diisopropyl azodicarboxylate (DIAD)–
TPP tandem failed, despite numerous experimental varia-
tions in solvents (THF, dioxane, NMP, DMF), molar
equivalents and sequence of addition of reagents, reaction
time and temperature. Even after 24 hours reaction time,
the conversion could not be increased to ca >20%.12 Next,
we tried to employ the ADDP–TBP combination (see
above), which is known to mediate alkylations for sys-
tems with a pKa>11.9 Similar experimental variations as
in the DIAD–TPP reagent tandem were performed, lead-
ing to some improvement in the overall alkylation pro-
cess. The highest conversions 1 2 were achieved (75%)
when 4.0 equivalents of each of the reagents (ADDP,
TBP, MeOH) were used (THF, r.t., 4 h). However, this
large excess of reagents caused problems in the subse-
quent work-up and purification. After considerable exper-
imentation we discovered that TMAD is the Mitsunobu
coupling reagent of choice for the selective N1-alkylation
of DHPMs. In combination with TBP it is more reactive
towards nucleophiles with a higher pKa value, as reported
by Tsunoda.10 Optimization studies demonstrated that uti-
lizing anhydrous dioxane as solvent showed a somewhat
better performance than THF, and if methanol as alkylat-
ing reagent was used the optimum conditions employed
The Mitsunobu reaction is a versatile method for the con-
version of aliphatic alcohols into alkylating agents in situ
and under mild conditions.8 Alkylations with the classical
Synlett 2002, No. 11, Print: 29 10 2002.
Art Id.1437-2096,E;2002,0,11,1901,1903,ftx,en;G23802ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1902
D. Dallinger, C. O. Kappe
LETTER
2.0 equivalents of MeOH, TMAD and TBP each. Under DHPM substrate at hand (entries 1–5), we next applied
these set of conditions complete and selective conversion this protocol to a small selection of 7 additional diverse
of 1 2 (Table 1, entry 1) was achieved within 1 hour at DHPM derivatives obtained from a recent library synthe-
room temperature. On prolonged exposure (>2 h) to ex- sis.6 Apart from methanol, other primary alcohols such as
cess Mitsunobu reagents, slow formation of small ethanol, propanol, hexanol, and benzylic type alcohols
amounts of the 1,3-dimethyl substituted DHPM was ob- were successfully utilized providing the desired N1-alky-
served.7 If other alcohols were used on the same DHPM lated DHPMs in moderate to good isolated yields (35–
substrate (Table 1, entries 2–5) somewhat different condi- 89%). Both electron withdrawing (entry 11) and donating
tions had to be employed (2.5 equiv TMAD–TBP, 5.0 substituents on the aromatic ring (entries 6–10, 12) were
equiv R4OH, 15 h, r.t.) in order to obtain complete conver- tolerated, and the alkylation procedure also worked well
sions. In all cases, the Mitsunobu alkylation took place se- for C4-alkyl- (entries 13 and 14) and even C4-unsubstitut-
lectively at the N1-position.13 Workup involved simple ed DHPM derivatives (entry 15). A variety of esters were
filtration from the reduced TMAD by-product, followed accepted at the C5 position of the DHPM core, including
by direct purification of the filtrate by silica gel flash chro- methyl, ethyl, and benzyl esters. In addition, 5-acetyl an-
matography.14
alogs (entries 16 and 17) also provided the corresponding
alkylated products in good yields. Note that longer alkyl
chains in the C6 position (entry 12) were also tolerated.
Having optimized conditions for selective Mitsunobu N1-
alkylations involving a variety of alcohols and one model
Table 1 Mitsunobu Reaction (TMAD–TBP) of Functionalized DHPMs 1 with Alcohols R4OHa
O
R2
O
R2
R4OH
H
O
H
O
TMAD, TBP
R1
N
R1
N
dioxane, rt
R3
N
R3
N
R4
2
H
1
Entry
1
R1
R2
Ph
Ph
Ph
Ph
Ph
R3
R4
Yield (%)b
89
EtO
EtO
EtO
EtO
EtO
MeO
MeO
MeO
EtO
EtO
EtO
EtO
EtO
EtO
PhCH2O
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
n-Pr
Me
Me
Me
Me
Me
Me
2
Et
66
3
n-Pr
n-hexyl
PhCH2
Me
42
4
35
5
61
6
3-Me-Ph
3-Me-Ph
3-Me-Ph
3,4-(MeO)2-Ph
3,4-(MeO)2-Ph
3-NO2-Ph
4-MeO-Ph
Me
87
7
n-Pr
3-F-PhCH2
Me
65
8
45
9
80
10
11
12
13
14
15
16
17
PhCH2
Me
54
65
Me
74
Me
88
Me
PhCH2
Me
59
H
76
Ph
Me
72
Me
Ph
Et
55
a For R4 = Me: 2.0 equiv MeOH, TMAD, and PBu3; dioxane, 1 h, r.t. For other alcohols: 5.0 equiv R4OH, 2.5 equiv TMAD and PBu3; dioxane,
15 h, r.t. For details, see ref.14
b Isolated yield of pure product after silica gel flash chromatography. All compounds were characterized on the basis of their 1H NMR and mass
spectroscopic data.
Synlett 2002, No. 11, 1901–1903 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Mitsunobu-Type Alkylation of 3,4-Dihydropyrimidin-2(1H)-ones
1903
(8) For reviews on the Mitsunobu reaction, see: (a) Mitsunobu,
O. Synthesis 1981, 1. (b) Hughes, D. L. Org. React. 1992,
42, 335. (c) Hughes, D. L. Org. Prep. Proced. Int. 1996, 28,
127.
(9) Tsunoda, T.; Yamamiya, Y.; Ito, S. Tetrahedron Lett. 1993,
34, 1639.
We were however unsuccessful in coupling secondary al-
cohols such as 2-propanol to DHPMs under any type of
reaction conditions. Even after 4 days of exposure to ex-
cess TMAD–TBP at room temperature or at elevated tem-
peratures (60–100 °C in dioxane, THF or NMP) no
conversion was observed. The use of the apparently more
reactive cyanomethylenetributylphosphonium salts also
proved to be ineffective.15
(10) Tsunoda, T.; Otsuka, J.; Yamamiya, Y.; Ito, S. Chem. Lett.
1994, 539.
(11) In general, examples found in the literature are limited to
relatively acidic sulfonamides or trifluoroacetamides. For
some recent examples involving amides, see: (a) Kozai, S.;
Takaoka, S.; Maruyama, T. Tetrahedron Lett. 2002, 43,
2633. (b) Evans, P. A.; Manangan, T. Tetrahedron Lett.
2001, 42, 6637. (c) Bombrun, A.; Casi, G. Tetrahedron Lett.
2002, 43, 2187. (d) Reichwein, J. F.; Liskamp, R. M. J.
Tetrahedron Lett. 1998, 39, 1243.
(12) Note that the use of high-temperature microwave chemistry
was unsuccessful here. For microwave-assisted Mitsunobu
alkylations, see: Steinreiber, A.; Stadler, A.; Mayer, S. F.;
Faber, K.; Kappe, C. O. Tetrahedron Lett. 2001, 42, 6283.
(13) 1H NMR spectroscopy (characteristic 3–5 Hz coupling
between C4-H and N3-H) readily allows one to distinguish
between N1-, N3- and O-alklyated DHPMs. For details and
the selective preparation of N3-alkylated DHPMs, see:
Kappe, C. O.; Roschger, P. J. Heterocycl. Chem. 1989, 26,
55.
(14) Typical Experimental Procedure (Outlined for Entry 5):
In a dry 5 mL reaction vial the appropriate DHPM
(R1 = EtO, R2 = Ph, R3 = Me; 26 mg, 0.10 mmol) was
dissolved in anhyd dioxane (0.5 mL) at 70 °C. After cooling
to r.t. benzyl alcohol (54 mg, 0.50 mmol, 52 L), TBP (51
mg, 0.25 mmol, 62 L) and TMAD (43 mg, 0.25 mmol)
were added. The vial was sealed, flushed with argon and the
reaction mixture shaken for 15 h at r.t. The white precipitate
that was formed was filtered off, and the crude reaction
mixture separated by silica gel flash chromatography
(DCM:EtOAc 1:1) providing 21.2 mg (61%) of N1-
alkylated DHPM as colorless crystals, mp 155 °C (lit.6 155–
156 °C). 1H NMR (DMSO-d6): = 1.09 (t, J = 7.1 Hz, 3 H),
2.36 (s, 3 H), 4.02 (q, J = 7.1 Hz, 2 H), 4.84 and 5.09 (2 d,
J = 16.6 Hz, 2 H), 5.24 (d, J = 3.2 Hz, 1 H), 7.06 (d, J = 7.0
Hz, 2 H), 7.22–7.35 (m, 8 H), 8.16 (d, J = 3.3 Hz, 1 H). MS
(APCI): m/z (%) = 351(28) [M+].
In conclusion, we have developed a simple procedure for
the selective N1-alkylation of Biginelli dihydropyrim-
idines (DHPMs) via a Mitsunobu protocol involving the
TMAD–TBP tandem as reagents. Therefore an additional
point of diversity can now be rapidly introduced on the
DHPM scaffold utilizing readily available primary alco-
hols as building blocks.
References
(1) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879.
(2) See for example: (a) Mayer, T. U.; Kapoor, T. M.; Haggarty,
S. J.; King, R. W.; Schreiber, S. L. Science 1999, 286, 971.
(b) Sidler, D. R.; Barta, N.; Li, W.; Hu, E.; Matty, L.;
Ikemoto, N.; Campbell, J. S.; Chartrain, M.; Gbewonyo, K.;
Boyd, R.; Corley, E. G.; Ball, R. G.; Larsen, R. D.; Reider,
P. J. Can. J. Chem. 2002, 80, 646. (c) Rovnyak, G. C.;
Atwal, K. S.; Hedberg, A.; Kimball, S. D.; Moreland, S.;
Gougoutas, J. Z.; O’Reilly, B. C.; Schwartz, J.; Malley, M.
F. J. Med. Chem. 1992, 35, 3254.
(3) For a recent review, see: Kappe, C. O. Eur. J. Med. Chem.
2000, 35, 1043.
(4) (a) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.
(b) Review: Kappe, C. O. Tetrahedron 1993, 49, 6937.
(5) Note that the successful use of N,N -disubstituted and N-
aryl-ureas in the Biginelli condensation is not well
documented in the literature. In our own hands, these
building blocks often produced mixtures of various
unidentified products along with only small amounts of the
desired dihydropyrimidones. See also: Kappe, C. O.;
Stadler, A. Org. Synth. 2003, 63, in press.
(6) Stadler, A.; Kappe, C. O. J. Comb. Chem. 2001, 3, 624; and
references cited therein.
(15) (a) Zaragoza, F.; Stephensen, H. J. Org. Chem. 2001, 66,
2518. (b) Tsunoda, T.; Ozaki, F.; Ito, S. Tetrahedron Lett.
1994, 35, 5081. (c) Tsunoda, T.; Nagino, C.; Oguri, M.; Ito,
S. Tetrahedron Lett. 1996, 37, 2459.
(7) (a) Khanina, E. L.; Andaburskaya, M. B.; Duburs, G.;
Zolotoyabko, R. M. Latv. PSR Zinat. Akad. Vestis, Kim. Ser.
1978, 197; Chem. Abstr. 1978, 89, 43319r. (b) Cho, H.;
Takeuchi, Y.; Ueda, M.; Mizuno, A. Tetrahedron Lett. 1988,
29, 5405.
Synlett 2002, No. 11, 1901–1903 ISSN 0936-5214 © Thieme Stuttgart · New York