Entry to nitrogen-containing heterocycles by based-promoted heterocyclization on allenylamides of l-α-aminoacids

Article abstract of DOI:10.1016/j.tetlet.2009.01.074

Allenylamides of Boc-protected α-aminoacids easily gave in basic medium heterocyclic products arising from attack of the NH group on the inside C-C double bond of the 1,2-diene moiety, namely imidazolidinones, pyrazinones, and a pyrrole compound. The micr

Full text of DOI:10.1016/j.tetlet.2009.01.074

Tetrahedron Letters 50 (2009) 1447–1449
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Entry to nitrogen-containing heterocycles by based-promoted
heterocyclization on allenylamides of L-a-aminoacids
*
Gianluigi Broggini , Simona Galli, Micol Rigamonti, Silvia Sottocornola, Gaetano Zecchi
Dipartimento di Scienze Chimiche e Ambientali, Università dell’Insubria, via Valleggio 11, 22100 Como, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Allenylamides of Boc-protected a-aminoacids easily gave in basic medium heterocyclic products arising
Received 20 November 2008
Revised 22 December 2008
Accepted 13 January 2009
Available online 19 January 2009
from attack of the NH group on the inside C–C double bond of the 1,2-diene moiety, namely imidazolid-
inones, pyrazinones, and a pyrrole compound. The microwave-assisted heterocyclization occurred
cleanly at C-b of the allenyl group with formation of pyrazin-2-ones having an endo- or exocyclic double
bond.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Allenes
Heterocyclization
Hydroamination
Microwave irradiation
Imidazolidinones
Pyrazinones
Pyrroles
The construction of nitrogen heterocycles is an important goal
in organic synthesis due to their occurrence in many natural sub-
stances as well as synthetic pharmaceuticals.1 Among the wide
range of substrates utilized as starting materials to this aim, allenes
constitute an interesting class of organic compounds with peculiar
chemical reactivity, having two cumulated double bonds.2
Intramolecular reactions of allenes may be achieved when the
substrate contains a nucleophilic moiety in a suitable position.
Among them, base-promoted reactions have been extensively
studied as a route to hetero- and carbocycle systems by using
nitrogen,3 oxygen4, or carbon5 nucleophiles. Transition metal-cata-
lyzed cyclization processes of allenes are also known.6
Within our research line on the development of novel methods
to build nitrogenated heterocycles, some years ago we considered
the behavior of amino- and sulfonylallenes as dipolarophiles in
1,3-dipolar cycloadditions.7 On continuing our interest in synthesis
and transformations of functionalized allenes, we have turned our
attention toward N-allenyl amides. In this Letter we describe the
by means of t-BuOK (2.5 equiv) in anhydrous THF, gave rise to alle-
nylamides 2 in near quantitative yields.8
While previously reported aminoallenes were revealed prone to
the formation of an internal C–C triple bond,7a compounds 2a–d
showed high stability making possible their storage for a long time.
The outcome of the allene formation was strongly dependent on
the reaction time. The exposure to the base for only one minute
Boc
R
NH
DCC, DMAP
+
OH
Me
CH2Cl2
48h; r.t.
HN
O
Me
γ
β
.
α
BocNH
R
BocNH
R
2.5 eq t-BuOK
N
N
Me
THF
1 min; r.t.
cyclization reactions of allenylamides derived from
As precursors for the allene derivatives 2, we first synthesized
propargylamides 1 starting from N-Boc-protected -aminoacids
a-aminoacids.
O
O
2a-d
1a-d
L-a
and methylpropargylamine by treatment with DCC (1.2 equiv)
and 4-(dimethylamino)pyridine (0.02 equiv) in dichloromethane
at room temperature (Scheme 1). The isomerization of 1, induced
a: R = i-Pr, 1: 95%, 2: 98%
b: R = i-Bu, 1: 96%, 2: 92%
c: R = Bn, 1: 94%, 2: 95%
d: R = Ph, 1: 97%, 2: 95%
* Corresponding author. Tel.: +39 0312386444; fax: +39 0312386449.
E-mail address: gianluigi.broggini@uninsubria.it (G. Broggini).
Scheme 1. Preparation of allenylamides 2a–d from natural
a
-aminoacids.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.074

1448
G. Broggini et al. / Tetrahedron Letters 50 (2009) 1447–1449
Me
Me
Boc
R
Boc
Boc
N
2.5 eq t-BuOK
N
N
2a-c
+
+
N
THF
see Table 1
N
N
Me
R
Me
R
Me
O
O
O
3a-c
4a-c
5b,c
a: R = i-Pr; b: R = i-Bu; c: R = Bn
Scheme 2. Heterocyclization of allenylamides 2a–c.
Table 1
Nitrogen-containing heterocycles produced via Scheme 2
Entry
R
Conditions
Yield%
3
4
5
a
a
b
b
c
i-Pr
i-Pr
i-Bu
i-Bu
Bn
rt, 4 h
MW irradiation, 30 min
rt, 4 h
MW irradiation, 30 min
rt, 4 h
MW irradiation, 30 min
32
—
9
—
8
29
95
28
89
36
72
—
—
25
—
27
—
c
Bn
—
promoted a clean formation of the allenyl products, while a longer
exposure to the base gave rise to complex mixtures of five- or six-
membered heterocyclic products arising from intramolecular at-
tack of the aminogroup on the carbon–carbon double bond.
With this evidence in hand, we tried to identify efficient condi-
tions for synthetically useful heterocyclization procedure and we
selected allene 2a to this purpose. The cleanest reaction, with lim-
ited formation of tarry products, was accomplished in the presence
of t-BuOK (2.5 equiv) in THF at room temperature for 4 h. Under
these conditions, we obtained the optically active 2-ethylyden-
imidazolidin-4-one 3a and 5-methyl-3,4-dihydro-pyrazin-2-one
4a in 32% and 29%, respectively (Scheme 2, Table 1).9 The Z-config-
uration of compound 3a is consistent with the observed mutual
NOE enhancements between the N-methyl group and the vinyl
hydrogen atom (3.3% and 5.8%). HPLC analysis with chiral column
of 3a and 4a, achieved in comparison to a sample of racemic mix-
ture, proved an enantiomeric purity better than 99.5%.10
Figure 1. Ortep drawing (at 30% probability level) of the molecular structure of
compound 6, highlighting the 2R,5S absolute configuration. C, gray; H, light gray; N,
blue; O, red.
Heterocyclization also occurred with allenes 2b,c according
to a more regioselective process. Despite their structures strictly
related to 2a, different ratios of five- and six-membered prod-
ucts were achieved. In fact, only small amounts of imidazolidi-
nones 3b,c (9% and 8%, respectively) were obtained, while
pyrazinones 4b,c were the major products besides their isomers
5b,c, so indicating preference for the C-b attack by the nucleo-
philic nitrogen.
The formation of the observed products can be rationalized as
follows. While the 1,4-diazine ring is resulted from the nucleo-
philic attack of the Boc-protected amine to the C-b of the allene
group, the formation of the endiamine five-membered product is
brought by an isomerization of the double bond of the first-gener-
ated cyclization product on the C-a.
However, the reactions just described, carried out at room tem-
perature, furnished the heterocyclic products in moderate yields
(see Table 1). Improved yields could not be achieved by refluxing
the solution due to the thermal decomposition of the substrates.
Hence, due to the ability of microwave irradiation to accelerate
several organic reactions,13 the heterocyclization processes were
tested in a microwave reactor. Under these conditions, the reac-
tions occurred cleanly in shorter times and higher yields giving
exclusively the six-membered ring products 4.14
It must be said that when the propargylamides 1a–c were sub-
mitted to a prolonged treatment in the presence of t-BuOK in order
to promote directly the heterocyclization process, complex mix-
tures with a high amount of tarry material were obtained.
Interestingly, a different behavior was observed for the allene
Compound 3a was smoothly and quantitatively transformed
into 2-ethyl-2-hydroxy-imidazolidin-4-one 611 by acid-catalyzed
addition of water to the carbon–carbon double bond (Scheme 3).
This process, which involves generation of a new stereocenter in
2-position of the imidazolidinone ring, gave only one diastereoiso-
mer and its absolute configuration was identified by X-ray diffrac-
tometric analysis to be 2R,5S (Fig. 1).12
Boc
OH
N
p-TSA (10 mol %)
3a
N
Me
THF/H2O 9:1
O
2d, arising from L-phenylglycine. In this case, the treatment with
t-BuOK at room temperature gave rise to the formation of only
one product, whose analytical and spectroscopic data accorded
with structure 715 (Scheme 4).
6 (98%)
Scheme 3. Transformation of imidazolidinone 3a.

G. Broggini et al. / Tetrahedron Letters 50 (2009) 1447–1449
1449
V. K.; Belsky, V. K.; Stash, A. I.; Zavodnik, V. E.; Stang, P. J. Eur. J. Org. Chem.
2005, 512; (e) Berg, T. C.; Bakken, V.; Gundersen, L.-L.; Petersen, D.
Tetrahedron 2006, 62, 6121; (f) Kitagaki, S.; Shibata, D.; Mukai, C.
Tetrahedron Lett. 2007, 48, 1735.
NHBoc
Me
Ph
O
t-BuOK (2.5 eq)
2d
5. Intramolecular reactions of allenes with carbon nucleophiles: (a) Kitagawa, O.;
Suzuki, T.; Fujiwara, H.; Fujita, M.; Taguchi, T. Tetrahedron Lett. 1999, 40, 4585;
(b) Mukai, C.; Ukon, R.; Kuroda, N. Tetrahedron Lett. 2003, 44, 1583; (c) Zafrani,
Y.; Cherkinsky, M.; Gottlieb, H. E.; Braverman, S. Tetrahedron 2003, 59, 2641; (d)
Mukai, C.; Kuroda, N.; Ukon, R.; Itoh, R. J. Org. Chem. 2005, 70, 6282.
6. (a) Bates, R. W.; Satcharoen, V. Chem. Soc. Rev. 2002, 31, 12; (b) Zimmer, R.;
Dinesh, C. U.; Nandanan, E.; Khan, F. A. Chem. Rev. 2000, 100, 3067; (c)
Widenhoefer, R. A.; Han, X. Eur. J. Org. Chem. 2006, 4555; (d) Ma, S. Pure Appl.
Chem. 2006, 78, 197.
THF
3 h; r.t.
N
Me
( )-7 (73%)
t-BuOK
7. (a) Broggini, G.; Zecchi, G. Gazz. Chim. Ital. 1996, 126, 479; (b) Broggini, G.;
Bruché, L.; Zecchi, G.; Pilati, T. J. Chem. Soc., Perkin Trans. 1 1990, 533; (c)
Broggini, G.; Zecchi, G. J. Chem. Soc., Perkin Trans. 1 1991, 1847; (d) Broggini, G.;
Molteni, G.; Zecchi, G. J. Org. Chem. 1994, 59, 8271; (e) Broggini, G.; Molteni, G. J.
Chem. Soc., Perkin Trans. 1 2000, 1685.
.
BocNH
_
Ph
N
Me
8. Selected examples of synthesis of allenes by isomerization of propargyl
derivatives: (a) Filippova, A. K.; Frolov, Y. L.; Lyashenko, G. S.; Modonov, V.
B.; Ivanova, N. A.; Kalikhman, I. D.; Voronkov, M. G.; Vyazankin, N. S. Russ.
Chem. Bull. 1986, 35, 1677; (b) Rochet, P.; Vatèle, J.-M.; Goré, J. Synthesis 1994,
795; (c) Hausherr, A.; Orschel, B.; Scherer, S.; Reissig, H.-U. Synthesis 2001,
1377.
O
A
Scheme 4. Heterocyclization of allenylamide 2d.
9. Procedure for cyclization of 2a: A solution of 2a (100 mg, 0.4 mmol) and t-BuOK
(112 mg, 1.0 mmol) in THF (8 mL) was stirred for 4 h at room temperature. The
solution was filtered off through a short silica gel path (hexane/AcOEt 4:1 as
eluent), and the solvent was evaporated under reduced pressure affording 3a
(32 mg, 32%) and 4a (29 mg, 29%).
The observed outcome can be due to the higher acidity of the
benzylic a-aminoacidic hydrogen of 2d with respect to 2a–c. Con-
sequently, in the presence of t-BuOK, the deprotonation of carbon
atom instead of the Boc-protected aminogroup is operative, fol-
lowed by the nucleophilic attack of the carbanion species A on
the sp-carbon. Such a mechanism well justifies the obtainment of
the pyrrolyl product in racemic form.
In conclusion, we have developed a simple procedure for build-
ing monocyclic five- and six-membered nitrogenated heterocycles
from new allenylamides of L-a-aminoacids under base conditions.
The moderate yields of the reactions performed at ambient tem-
perature could be significantly increased by applying microwave
activation. Further investigations, mainly based on the use of tran-
sition metals, are in progress in order to achieve more selective
reactions and differently substituted products.
Compound 3a. Pale yellow oil. 1H NMR (400 MHz, CDCl3): d 0.89 (d, J = 6.9 Hz,
3H), 1.01 (d, J = 6.9 Hz, 3H), 1.51 (s, 9H), 1.71 (d, J = 7.1 Hz, 3H), 2.26 (dqq,
J = 3.5 Hz, 6.9 Hz, 6.9 Hz, 1H), 2.96 (s, 3H), 4.26 (d, J = 3.5 Hz, 1H), 4.44 (q,
J = 7.1 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 13.3 (q), 17.3 (q), 19.2 (q), 26.2 (q),
28.6 (q), 32.8 (d), 66.7 (d), 82.3 (s), 89.2 (d), 138.6 (s), 152.7 (s), 170.5 (s). IR
(Nujol): 1685, 1710 cmꢀ1. ½a D23
ꢁ
+3.7 (c 0.03, CHCl3).
Compound 4a. Colorless oil. 1H NMR (400 MHz, CDCl3): d 0.92 (d, J = 6.7 Hz, 3H),
0.98 (d, J = 6.7 Hz, 3H), 1.47 (s, 9H), 1.83 (m, 1H), 2.06 (s, 3H), 3.02 (s, 3H), 4.34
(m, 1H), 5.47 (s, 1H). 13C NMR (100 MHz, CDCl3): d 18.0 (q), 19.4 (d), 28.3 (q),
28.6 (q), 33.2 (q), 63.8 (d), 81.8 (s), 117.8 (d), 119.7 (s), 153.4 (s), 166.1 (s). IR
(Nujol): 1684, 1706 cmꢀ1. ½a D23
ꢁ
+103.0 (c 0.70, CHCl3).
10. The enantiopurity was determined by HPLC (OD-H column, 4.6 ꢂ 250 mm,
mobile phase of 70/30 hexane/EtOH, flow rate 1.0 mL/min) with a detector at
231 nm.
11. Compound 6: Mp 121–122 °C. 1H NMR (400 MHz, CDCl3): d 0.93 (X part of ABX3
system, J = 7.5 Hz, 3H), 1.00 (d, J = 6.9 Hz, 3H), 1.17 (d, J = 6.9 Hz, 3H), 1.52 (s,
9H), 2.07 (A part of ABX3 system, J = 14.9 Hz, 7.5 Hz, 1H), 2.28 (m, 1H), 2.51 (B
part of ABX3 system, J = 14.9 Hz, 7.5 Hz, 1H), 2.87 (s, 3H), 3.97 (d, J = 4.1 Hz,
1H), 4.58 (s br, 1H, missing after deuteriation). 13C NMR (100 MHz, CDCl3): d
9.8 (q), 17.5 (q), 20.2 (d), 24.8 (q), 28.7 (q), 30.9 (t), 31.5 (d), 63.6 (d), 82.4 (s),
Acknowledgments
100.6 (s), 154.7 (s), 170.6 (s). IR (Nujol): 1680, 1709, 3380 cmꢀ1. ½a D23
ꢁ
+7.1 (c
TheauthorsgratefullyacknowledgetheMinisterodell’Università
e della Ricerca for financial support and for the PhD fellowships to
S.S. (Progetto Giovani 2004) and M.R. (Progetto Giovani 2006).
0.03, CHCl3).
ꢀ
12. X-ray crystallography for 6: triclinic, space group P1, a = 5.917(3) Å, b = 9.257(2)
Å, c = 14.909(4) Å, = 88.56(2)°, b = 84.26(3)°,
= 84.60(2)°, V = 808.8(5) Å3,
Z = 2, F(000) = 312, (Mo–K The R, wR
= 1.176 g cmꢀ3 ) = 0.086 mmꢀ1
figures of merit reached final values of 0.043, 0.111 for the 2270 observed
reflections (I > 2 (I)), and 0.059, 0.119 for all of the 2913 unique reflections,
a
c
a
q
,
l
.
References and notes
r
182 parameters. Goodness of fit, highest peak, and deepest hole reached final
values of 1.049, 0.195 e Åꢀ3 and ꢀ0.216 e Åꢀ3. Crystallographic data (excluding
structure factors) for the structure in this Letter have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication no.
709855. Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-
mail: deposit@ccdc.cam.ac.uk).
1. For example, see: Progress in Heterocyclic Chemistry; Gribble, G. W., Gilchrist, T.
L., Eds.; Pergamon: Oxford, 2000; Vol. 12,.
2. (a) Schuster, H. F.; Coppola, G. M. Allenes in Organic Synthesis; Wiley: New York,
1984; (b) Krause, N.; Hashmi, A. S. K. Modern Allene Chemistry; Wiley-VCH:
Weinheim, 2004.
3. Intramolecular reactions of allenes with nitrogen nucleophiles: (a) Amombo,
M. O.; Hausherr, A.; Reissig, H.-U. Synlett 1999, 1871; (b) Ohno, H.; Ando, K.;
Hamaguchi, H.; Takeoka, Y.; Tanaka, T. J. Am. Chem. Soc. 2002, 124, 15255; (c)
Mukai, C.; Kobayashi, M.; Kubota, S.; Takahashi, Y.; Kitagaki, S. J. Org. Chem.
2004, 69, 2128; (d) Hamaguchi, H.; Kosaka, S.; Ohno, H.; Tanaka, T. Angew.
Chem., Int. Ed. 2005, 44, 1513; (e) Kaden, S.; Brockmann, M.; Reissig, H.-U. Helv.
Chim. Acta 2005, 88, 1826; (f) Ohno, H.; Kadoh, Y.; Nobutaka, F.; Tanaka, T. Org.
Lett. 2006, 8, 947; (g) Kuroda, N.; Takahashi, Y.; Yoshinaga, K.; Mukai, C. Org.
Lett. 2006, 8, 1843; (h) Chowdhury, M. A.; Reissig, H.-U. Synlett 2006, 2383.
4. Intramolecular reactions of allenes with oxygen nucleophiles: (a) Pairaudeau,
G.; Parsons, P. J.; Underwood, J. M. J. Chem. Soc., Chem. Commun. 1987, 1718;
(b) Mukai, C.; Yamashita, H.; Hanaoka, M. Org. Lett. 2001, 3, 3385; (c) Mukai,
C.; Ohta, M.; Yamashita, H.; Kitagaki, S. J. Org. Chem. 2004, 69, 6867; (d) Brel,
13. Kappe, O. Angew. Chem., Int. Ed. 2004, 43, 6250.
14. Procedure for cyclization of 2a under microwave irradiation: A solution of 2a
(100 mg, 0.4 mmol) and t-BuOK (112 mg, 1.0 mmol) in THF (5 mL) was heated
for 30 min at 50 °C and 250 Watt in a CEM Discover microwave reactor. The
solution was filtered off through a short silica gel path (hexane/AcOEt 4:1 as
eluent), and the solvent was evaporated under reduced pressure affording 4a
as a colorless oil (95 mg, 95%).
15. Compound 7. Pale yellow oil. 1H NMR (400 MHz, CDCl3): d 1.42 (s, 9H), 1.74 (d,
J = 1.6 Hz, 3H), 3.01 (s, 3H), 5.24 (s br, 1H, missing after deuteriation), 6.24 (q,
J = 1.6 Hz, 1H), 7.37 (m, 5H). 13C NMR (100 MHz, CDCl3): d 10.9 (q), 24.3 (q),
29.8 (q), 68.1 (s), 80.8 (s), 119.6 (s), 126.2 (d), 129.0 (d), 129.3 (d), 129.5 (d),
137.5 (s), 154.4 (s), 177.8 (s). IR (Nujol): 1697, 1712 cmꢀ1
.