Microwave-assisted synthesis of novel (5-nitropyridin-2-yl)alkyl and (5-nitropyridin-3-yl)alkyl carbamates

Article abstract of DOI:10.1021/jo802439d

A straightforward approach to novel (5-nitropyridin-2-yl)alkyl and (5-nitropyridin-3-yl)alkyl carbamate building blocks is presented in this study. Their construction is achieved by condensation of N-carbamate a- and β-amino carbonyl derivatives with l-methyl-3,5-dinitro-2-pyridone 1 under microwave irradiation. Judiciously chosen modifications in the nature of the parent carbonyl starting material has influenced the regiochemical outcome of the reaction and allowed an efficient access to novel nitrogen-containing scaffolds. Compounds sharing morphological similarities have been gathered in three libraries differing from each other in a single structural parameter.

Full text of DOI:10.1021/jo802439d

Microwave-Assisted Synthesis of Novel (5-Nitropyridin-2-yl)alkyl
and (5-Nitropyridin-3-yl)alkyl Carbamates
Christophe Henry,*,† Andreas Haupt, and Sean C. Turner*
Neuroscience DiscoVery Research, Abbott GmbH & Co. KG, P.O. Box 210805,
67008 Ludwigshafen, Germany
christophe.henry@4sc.com
ReceiVed NoVember 1, 2008
A straightforward approach to novel (5-nitropyridin-2-yl)alkyl and (5-nitropyridin-3-yl)alkyl carbamate
building blocks is presented in this study. Their construction is achieved by condensation of N-carbamate
R- and ꢀ-amino carbonyl derivatives with 1-methyl-3,5-dinitro-2-pyridone 1 under microwave irradiation.
Judiciously chosen modifications in the nature of the parent carbonyl starting material has influenced the
regiochemical outcome of the reaction and allowed an efficient access to novel nitrogen-containing
scaffolds. Compounds sharing morphological similarities have been gathered in three libraries differing
from each other in a single structural parameter.
Introduction
biological and pharmaceutical importance like the well-known
manzamine-related alkaloids,5 the recently isolated shish-
ijimicins,6 or the eudistomins.7
Chemical entities possessing a ꢀ-aminopyridine core structure
are in themselves attractive building blocks that are challenging
Bioactive structures incorporating a 3-aminopyridine motif
constitute a significant class of pharmaceutical compounds, and
to date, nearly 100 marketed and developmental pharmaceutics
featuring this pattern have been reported.1 They cover a broad
spectrum of activity and include, for instance, promising
cytotoxic anticancer therapeutics,2 potent angiotensin-receptor
antagonists,3 and histamine-receptor antagonists.4 The ꢀ-ami-
nopyridine core can also be considered as a subunit of more
complex nitrogen-containing polycyclic systems commonly
known as ꢀ-carbolines. These pyrido[3,4-b]indoles are sub-
structures found in some interesting natural products with
(5) El Sayed, K. A.; Kelly, M.; Kara, U. A. K.; Ang, K. K. H.; Katsuyama,
I.; Dunber, D. C.; Khan, A. A.; Hamann, M. T. J. Am. Chem. Soc. 2001, 123,
1804–1808, and references therein. .
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Ranes, E.; Riha, J.; Svensen, H. Acta Chem. Scand. 1999, 53, 141–144. (c)
Murashima, T.; Nishi, K.; Nakamoto, K.-I.; Kato, A.; Tamai, R.; Uno, H.; Ono,
N. Heterocycles 2002, 58, 301–310. (d) Murugan, R.; Scriven, E. F. V.; Hillstrom,
G. F.; Ghoshal, P. K. PCT Int. Appl. WO 02/090328 A1; Chem. Abstr. 2002,
137, 352895. (e) Provencal, D. P.; Gesenberg, K. D.; Wang, H.; Escobar, C.;
Wong, H.; Brown, M. A.; Staab, A. J.; Pendri, Y. R. Org. Process Res. DeV.
2004, 8, 903–908. (f) Katritzky, A. R.; Scriven, E. F. V.; Majumder, S.;
Akhmedova, R. G.; Vakulenko, A. V.; Akhmedov, N. G.; Murugan, R.; Abboud,
K. A. Org. Biomol. Chem. 2005, 3, 538–541.
† Present address: 4SC AG, Am Klopferspitz 19a, 82152 Planegg-Martinsried,
Germany. Fax: 0049 89 70 07 63 29.
(1) Data collected in the Investigational Drugs database, copyright Thomson
Reuters.
(2) Gu, W.-Z.; Tahir, S. K.; Wang, Y.-C.; Zhang, H.-C.; Cherian, S. P.;
O’Connor, S.; Leal, J. A.; Rosenberg, S. H.; Ng, S.-C. Eur. J. Cancer 1999, 35,
1394–1401.
(3) Quan, M. L.; Chiu, A. T.; Ellis, C. D.; Wong, P. C.; Wexler, R. R.;
Timmermans, P. B. M. W. M. J. Med. Chem. 1995, 38, 2938–2945.
(4) Ganellin, C. R.; Hosseini, S. K.; Khalaf, Y. S.; Tertiuk, W.; Harrang,
J.-M.; Garbarg, M.; Ligneau, X.; Schwartd, J.-C. J. Med. Chem. 1995, 38, 3342–
3350.
(9) (a) Marcoux, J.-F.; Corley, E. G.; Rossen, K.; Pye, P.; Wu, J.; Robbins,
M. A.; Davies, I. W.; Larsen, R. D.; Reider, P. J. Org. Lett. 2000, 2, 2339–
2341. (b) Davies, I. W.; Marcoux, J.-F.; Wu, J.; Palucki, M.; Corley, E. G.;
Robbins, M.; Tsou, N.; Ball, R. G.; Dormer, P.; Larsen, R. D.; Reider, P. J.
Org. Chem. 2000, 65, 4571–4574.
1932 J. Org. Chem. 2009, 74, 1932–1938
10.1021/jo802439d CCC: $40.75 2009 American Chemical Society
Published on Web 01/28/2009

MicrowaVe-Assisted Synthesis
SCHEME 1
to build. Very few examples in the literature report protocols
for the direct ꢀ-nitration of preformed pyridine rings.8a-d While
the inductive effect of the nitrogen atom allows both the R-
and γ-activations in nucleophilic substitution, pyridine undergoes
electrophilic substitution reactions at the nitrogen atom and at
the ꢀ-position. However, it is also a π-deficient heterocycle and
its electronic profile tends to neutralize the C-3 carbon, which
is hard to attack without the assistance of additional activating
substituents connected to the ring.8e Recently, Katritzky and
co-workers reported a remarkable preparation of ꢀ-nitropyridines
using the system nitric acid/trifluoroacetic anhydride.8f Never-
theless, the nitration steps remain somewhat difficult or unpleas-
ant to carry out, and the yields drop dramatically with increasing
molecular complexity. In addition, nitrations occur in strongly
acidic media, which are often incompatible with sensitive
functional groups. An alternative approach addressing this issue
and circumventing the troublesome nitration step would be to
construct the pyridine core by condensing an intermediate
bearing a nitro group with suitable carbonyl compounds in the
presence of ammonia. Among the reagents typically used for
this type of cyclization are the nitro-vinamidinium salts
developed by Merck9a,b and the 3,5-dinitro-1-methyl-2-pyridone
1 reported by Tohda.10 Although the latter developed a rapid
and powerful method to access ꢀ-nitropyridines, few examples
of its application in organic synthesis have been disclosed in
the literature to date. In addition, the scope of this reaction has
been mostly limited to cyclic symmetrical ketones.11a-h
In connection with a medicinal chemistry program, we
became interested in elaborating novel pyridine-based chemo-
types presenting a rigidified arrangement between two nitrogen
atoms and allowing fine-tuning of the position of a third nitrogen
via a carbon spacer. They can be organized into three generic
families of compounds I, II, and III that possess close topology
and differ from each other in a sole parameter. Hence, the spatial
display of the three key atoms would be directly related either
by a 180° “flip” of the heterocyclic ring, a variation of one
carbon in the chain length, or by a 60° hourly rotation of the
two nitrogen atoms incorporated in the core structure
(Scheme 1).
SCHEME 2
SCHEME 3
to condense the 3,5-dinitro-1-methyl-2-pyridone 1 with a variety
of N-carbamate R- and ꢀ-amino carbonyls (Scheme 2).
The formation of the ꢀ-nitropyridine ring with 1 proceeds
only with starting materials featuring at least one CH2 motif
flanking the carbonyl function. A plausible mechanism involves
the abstraction of a first adjacent proton, leading to an enol
species capable of reacting with a complex formed after addition
of a molecule of ammonia to the pyridone system. Next, the
departure of a second geminal proton is necessary for the
formation of a cyclic enamine intermediate that finally rearo-
matizes to give the pyridine ring.10 According to this mechanistic
sequence, the nature of the N-carbamate R- and ꢀ-amino
carbonyl will control the position of the additional nitrogen-
containing skeleton branched to the ꢀ-nitropyridine. In this
paper, we report our efforts in designing and preparing three
collections of novel (5-nitropyridin-2-yl)alkyl carbamates I and
II and (5-nitropyridin-3-yl)alkyl carbamates III using microwave
synthesis (Scheme 3).
Therefore, we envisaged to construct molecular templates
derived from a ꢀ-nitropyridine unit fused with an additional
carbon frame bearing a carbamate group. In addition, the
selection of both a nitro group and a carbamate group on the
same molecule would circumvent any problem of orthogonal
reactivity at a later point. Hence, our retrosynthetic plan led us
(10) Tohda, Y.; Eiraku, M.; Nakagawa, T.; Usami, Y.; Ariga, M.; Kawashima,
T.; Tani, K.; Watanabe, H.; Mori, Y. Bull. Chem. Soc. Jpn. 1990, 63, 2820–
2827.
(11) (a) Takada, S.; Sasatani, T.; Chomei, N.; Adachi, M.; Fujishita, T.; Eigyo,
M.; Murata, S.; Kawasaki, K.; Matsushita, A. J. Med. Chem. 1996, 39, 2844–
2851. (b) Harling, J. D.; Harrington, F. P.; Thompson, M. Synth. Commun. 2001,
31, 787–797. (c) Ananthan, S.; Kezar, H. S.; Saini, S. K.; Khare, N. K.; Davis,
P.; Dersch, C. M.; Porreca, F.; Rothman, R. B. Bioorg. Med. Chem. Lett. 2003,
13, 529–532. (d) Austin, N. E.; Hadley, M. S.; Harling, J. D.; Harrington, F. P.;
Macdonald, G. J.; Mitchell, D. J.; Riley, G. J.; Stean, T. O.; Stemp, G.; Stratton,
S. C.; Thompson, M.; Upton, N. Bioorg. Med. Chem. Lett. 2003, 13, 1627–
1629. (e) Jiao, R.; Butora, G.; Goble, S. D.; Guiadeen, D.; Mills, S. G.; Moriello,
G.; Pasternak, A.; Tang, C.; Yang, L.; Zhou, C.; Kothandaraman, S.; Moyes, C.
U.S. Patent Appl. US 2005/0107422 A1; Chem. Abstr. 2005, 142, 482030. (f)
Nishiwaki, N.; Tatsumichi, H.; Tamura, M.; Ariga, M. Lett. Org. Chem. 2006,
3, 629–633. (g) Vara Prasad, J. V. N.; Boyer, F. E.; Chupak, L.; Dermyer, M.;
Ding, Q.; Gavardinas, K.; Hagen, S. E.; Huband, M. D.; Jiao, W.; Kaneko, T.;
Maiti, S. N.; Melnick, M.; Romero, K.; Patterson, M.; Wu, X. Bioorg. Med.
Chem. Lett. 2006, 16, 5392–5397. (h) Drescher, K.; Haupt, A.; Unger, L.; Turner,
S. C.; Braje, W.; Grandel, R.; Henry, C. PCT Int. Appl. WO 2006/040178 A1;
Chem. Abstr. 2006, 144, 412247.
Results and Discussion
Most of the requisite carbonyl starting materials were not
commercially accessible and had to be prepared. According to
a classical procedure starting from commercially available
carboxylic acids, methyl ketones 2a-d and 3a-c (Table 1,
entries 1-7), 8a, and 9a (Table 3, entries 1 and 4) as well as
aldehyde 6b (Table 2, entry 2) were synthesized in good overall
(12) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815–3818.
(b) Fehrentz, J.-A.; Castro, B. Synthesis 1983, 8, 676–678.
J. Org. Chem. Vol. 74, No. 5, 2009 1933

Henry et al.
TABLE 1. Condensation of N-Carbamate r- and ꢀ-Amino Methyl
Ketones 2 and 3 with 1
TABLE 2. Condensation of N-Carbamate ꢀ-Amino Aldehydes 6
with 1
a Isolated yields. b Aldehyde 6b was used directly without any further
purification in the condensation reaction, therefore yield for two steps.
initially chosen in order to define an optimal and general
protocol.17 When a mixture of 2a and 1 was heated under
conventional thermal conditions in the presence of NH3 in
methanol at 90 °C for 20 min, the nitropyridine 4a was isolated
in 37% yield. Longer reaction times or higher temperatures gave
no significant improvement and, therefore, prompted us to
explore the use of microwave technology.
Thus, when the same mixture was reacted at 90 °C for 20
min under microwave irradiation, the conversion was cleaner
and a substantial increase in yield (95%) was noticed. To explore
the substrate tolerance of this reaction, we extended the above
methodology to several additional carbonyl substrates. As can
be seen from the results summarized in Table 1, the products
of condensation were readily prepared and furnished us with
six structures from chemotypes I or II. Hence, good to excellent
yields were obtained for either five-membered nitrogen-contain-
ing rings 4a, 4b, and 4d (Table 1, entries 1, 2, and 4) or
piperidine derivatives 4c and 5b (Table 1, entries 3 and 6).
By comparing the results for condensation of methyl ketones
2a and 2b with 1, one can note that the presence of an additional
heteroatom (Table 1, entry 2) on the carbonyl partner seems to
affect slightly the rate of conversion. Interestingly, when the
transformation was conducted with a substrate featuring an
a Isolated yields.
yields via formation of the Weinreb amide followed by
displacement with MeMgBr or reaction with DIBAL-H.12a,b The
preparation of the cyclic intermediates 9b, 9c, and 9d (Table 3,
entries 5-7) involved aza-Michael addition of a benzyl car-
bamate group onto the ꢀ-position of an enone π-system. In many
reports, this reaction proceeds smoothly when catalyzed by
transition metal and metal salts such as Bi(NO3)3, PtCl4, or
Cu(OTf)2.13a-c In our hands, Bi(NO3)3 turned out to be the most
efficient reagent, providing us with the desired N-carbamate-
ꢀ-cycloketones in good to excellent yields (Scheme 4). Access
to aldehyde 6c (Table 2, entry 3) was achieved by Dess-Martin
periodinane oxidation of the corresponding primary alcohol.14
Acetyl carbamates 215,16 and 3 should undergo the cyclization
process and furnish only one regioisomer, namely, a (5-
nitropyridin-2-yl)alkyl carbamate. The condensation of the
pyridone 1 with the methyl ketone 2a (Table 1, entry 1) was
(13) (a) Kobayashi, S.; Kakumoto, K.; Sugiura, M. Org. Lett. 2002, 4, 1319–
1322. (b) Wabnitz, T. C.; Spencer, J. B. Tetrahedron Lett. 2002, 43, 3891–
3894. (c) Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68, 2109–2114.
(14) Rouden, J.; Seitz, T.; Lemoucheux, L.; Lasne, M.-C. J. Org. Chem.
2004, 69, 3787–3793.
(15) For the preparation of 2a, see: Goldstein, S. W.; Overman, L. E.;
Rabinowitz, M. H. J. Org. Chem. 1992, 57, 1179–1190.
(16) For the preparation of 2c, see: Aoyagi, S.; Wang, T.-C.; Kibayashi, C.
J. Am. Chem. Soc. 1993, 115, 11393–11409.
(17) As an initial study, we set out to investigate the role of reaction solvent.
In addition to the solvent medium NH3/MeOH, which was typically used in
previous syntheses for this condensation, additional commercially available
solutions were also tested as ammonia sources. Except for NH3/EtOH, which
furnished comparable results to those obtained in MeOH, reactions conducted
in NH3/i-propanol or in NH3/dioxane resulted in the formation of only trace
amounts of the desired ꢀ-nitropyridines. The low rate of conversion was mainly
due to the poor solubility of 1, and subsequent solvent combinations with CH3CN,
DMF, or pyridine did not significantly improve the condensation outcomes.
1934 J. Org. Chem. Vol. 74, No. 5, 2009

MicrowaVe-Assisted Synthesis
TABLE 3. Condensation of Nonsymmetrical N-Carbamate r- and ꢀ-Amino Ketones 8 and 9 with 1
a Isolated yields. b Product 11b detected but not isolated. c Obtained after condensation performed at 120 °C.
SCHEME 4
exocyclic nitrogen (Table 1, entry 4), the reaction furnished
exclusively the desired product 5a, but the yield did not exceed
53%.
We next undertook to react 1 with several N-carbamate
ꢀ-amino aldehydes 6 enolizable only at the R-position to
selectively prepare (5-nitropyridin-3-yl)alkyl carbamates. In
contrast to the previously described methyl ketones depicted
in Table 1, the condensation of 1 with aldehydes resulted in
a structural permutation of the nitrogen-containing moiety
from the 2-position to the 3-position to afford 3-alkyl-5-
nitropyridines of type III. One of the drawbacks of using
aldehydes is their relative instability and propensity for
polymerization reactions. As summarized in Table 2, we were
able to prepare three novel structures 7a, 7b, and 7c in
moderate yields. We thought that the microwave-assisted
condensation would benefit from the thermal effect and
J. Org. Chem. Vol. 74, No. 5, 2009 1935

Henry et al.
SCHEME 5. Proposed Mechanism for the Formation of 12d
prevent side reactions.18 Despite variation of parameters such
as reaction time or temperature, no significant improvement
in term of yields could be obtained. In addition, direct transfer
of energy to the solvent in sealed vessels competes with
superheating, which might lead to the formation of undesired
side products frequently encountered with aldehyde chem-
istry. Nevertheless, the low isolated yield observed for
nitropyridine 7b (Table 2, entry 2) can be probably attributed
to the relative impurity of the aldehyde 6b, which was used
without any further purification after its preparation.19
Finally, we applied our procedure to nonsymmetrical ketones
featuring two CH2 motifs at both sides of the carbonyl function.
According to the proposed mechanism previously discussed, we
envisioned that nonsymmetrical starting materials should provide
us with two different nitropyridine products. The condensation
of pyridone 1 with the secondary carbamate 8a20 (Table 3, entry
1) was first examined. As expected, the two nitropyridine
derivatives 10a and 11a were obtained in a good yield of 74%
and in a ratio 1/2.5, respectively. Interestingly, this ratio was
completely inverted with the cyclic counterpart 8c (Table 3,
entry 3), but the yield of isolated products 10c and 11c dropped
to 30%. Surprisingly, when the condensation was carried out
with pyrrolidin-3-one 8b (Table 3, entry 2), the observed ratio
for the two possible products was further shifted and only the
desired nitropyridine derivative 10b was isolated in a moderate
yield. The second regioisomer 11b could hardly be detected by
TLC analysis and LC-MS spectroscopy. The two undesired
products 11a and 11c were isolated and characterized. As
predicted, each of the N-carbamate ꢀ-amino ketones 9a-c
(Table 3, entries 4-6)13,21,22 afforded two structures of type I
and III with excellent yields and with proportions ranging from
2/1 to 3/1. It is likely that the bulky Boc and Cbz protecting
groups in the cyclic series interact with the substituents on the
preformed pyridine ring and therefore account for the predomi-
nant formation of both 12b and 12c. The influence of the same
steric factors reinforced by the deficit of one carbon can also
be used to explain the similar regioselectivity observed for the
pairs 10b/11b and 10c/11c (Table 3, entries 2 and 3). Further-
more, when comparing the overall yields obtained for endocyclic
versus exocyclic nitrogen atoms, it is likely that the nitrogen
atom of the R-amino ketones significantly impacts the acidity
of the hydrogen atoms and therefore hinders the enol formation.
One can also postulate that the results observed with the acyclic
ketones 8a and 9a (Table 3, entries 1 and 4) could be explained
by the formation of less rigid intermediates accompanied by
reduced sensitivity to the internal geometry. All pairs of isomers
could be separated by normal or reversed phase chromatography
and were fully characterized. It is important to note that, while
only one study reports the use of this methodology for the
preparation of bicyclic structures featuring an intracyclic
nitrogen atom starting from symmetric cycloketones,11b the
preparation of ꢀ-nitropyridine systems from nonsymmetric
cycloketones bearing an exocyclic nitrogen has not been
previously reported.
Microwave-assisted chemistry has not only demonstrated a
marked enhancement in terms of yield and short reaction times
in organic synthesis but it also allows access to reaction products
that are not attainable under classical heating conditions.23,24
As an illustration, when the condensation was attempted with
the ketone 9d (Table 3, entry 7)25 under classical heating, only
the isomer 13d was isolated in a low 18% yield. No trace
of the second theoretical heterocycle 12d was observed even at
higher reaction temperatures.
The origin of the selectivity can be rationalized by the
presence of the oxygen heteroatom that completely shuts down
the deprotonation process at this side of the ketone group.
(18) Kuhnert, N. Angew. Chem., Int. Ed. 2002, 41, 1863–1866.
(19) Toujas, J.-L.; Jost, E.; Vaultier, M. Bull. Soc. Chim. Fr. 1997, 134, 713–
717.
(20) Nagafuji, P.; Cushman, M. J. Org. Chem. 1996, 61, 4999–5003.
(21) For the preparation of 9a, see: (a) Ninomiya, K.; Shioiri, T.; Yamada,
S. Tetrahedron 1974, 30, 2151–2157. (b) Gaunt, M. J.; Spencer, J. B. Org. Lett.
2001, 3, 25–28.
(22) For the preparation of 9b, see: (a) Xu, L.-W.; Xia, C.-G.; Hu, X.-X.
Chem. Commun. 2003, 20, 2570–2571. (b) Xu, L.-W.; Xia, C.-G. Tetrahedron
Lett. 2004, 45, 4507–4510.
(23) (a) Mavandadi, F.; Lidstrom, P. Curr. Top. Med. Chem. 2004, 4, 773–
792. (b) Kappe, C. O.; Stadler, A. In MicrowaVes in Organic and Medicinal
Chemistry; Mannhold, R., Kubinyi, H., Folkers, G., Eds.; Wiley-VCH: Werlag
GmbH & Co. KGaA: Weinheim, Germany, 2005. (c) Kappe, C. O.; Dallinger,
D. Nat. ReV. Drug DiscoVery 2006, 5, 51–63.
(24) For examples of microwave-assisted synthesis of heterocycles, see: (a)
Zhao, Z.; Wisnoski, D. D.; Wolkenberg, S. E.; Leister, W. H.; Wang, Y.;
Lindsley, C. W. Tetrahedron Lett. 2004, 45, 4873–4876. (b) Siu, J.; Baxendale,
I. R.; Ley, S. V. Org. Biomol. Chem. 2004, 2, 160–167. (c) Sandin, H.; Swanstein,
M.-L.; Wellner, E. J. Org. Chem. 2004, 69, 1571–1580. (d) Sparks, R. B.; Combs,
A. P. Org. Lett. 2004, 6, 2473–2475. (e) Schirok, H. J. Org. Chem. 2006, 71,
5538–5545.
(25) The preparation of 9d started from the corresponding 2H-pyran-3(6H)-
one, which had to be synthesized according to: Eiden, F.; Wanner, K. T. Arch.
Pharm. 1985, 318, 548–555.
1936 J. Org. Chem. Vol. 74, No. 5, 2009

MicrowaVe-Assisted Synthesis
1H), 4.04 (m, 2H), 6.09 (m, 1H), 7.38 (d, J ) 8.6 Hz, 1H), 8.44
(d, J ) 7.3 Hz, 1H), 9.35 (d, J ) 2.3 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ (mixture of rotamers) 27.2 (3C), 28.8, 29.7, 49.7,
63.8, 80.2, 118.2, 130.9, 142.1, 144.0, 151.9, 152.4, 166.9, 167.3.
Anal. Calcd for C13H17N3O4S: C, 50.15; H, 5.50; N, 13.50; O, 20.55;
S, 10.30. Found: C, 50.38; H, 5.71; N, 13.09; O, 20.14; S, 10.39.
tert-Butyl 2-(5-nitropyridin-2-yl)cyclopentylcarbamate (5a):
Obtained as a white solid; 1H NMR (400 MHz, CDCl3) δ 1.34 (s,
9H), 1.62 (m, 1H), 1.88 (m, 2H), 2.02 (m, 1H), 2.21 (m, 2H), 3.17
(m, 1H), 4.14 (quint, J ) 8.0 Hz, 1H), 4.68 (d, J ) 5.9 Hz, 1H),
7.43 (d, J ) 8.3 Hz, 1H), 8.37 (dd, J ) 8.5, 2.5 Hz, 1H), 9.35 (d,
J ) 1.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 22.8, 28.3 (3C),
31.3, 32.9, 54.7, 58.6, 79.3, 122.3, 131.1, 142.7, 144.7, 155.2, 169.9;
HRMS calcd for C15H22N3O4 308.1610, found 308.1601.
Nevertheless, we were pleased to observe that the same reaction
sequence carried out under microwave irradiation at 120 °C for
10 min afforded a mixture of two ꢀ-nitropyridines 12d and 13d
in a 64% yield, the ratio of 7.5/1 being favorable toward the
isomer 13d. On the basis of experimental observations, it is
reasonable to imagine that the initial enol formation may occur
to some extent to yield a Meisenheimer adduct in equilibrium
with the imine form that failed to undergo the second proton
abstraction under classical conditions (Scheme 5). It is likely
that the different rate of heating and the higher reaction
temperature under microwave conditions are responsible for the
observed formation of the second oxygen-containing bicyclic
system 12d.
Benzyl (5-nitropyridin-3-yl)methylcarbamate (7a): Obtained
as a light yellow solid; 1H NMR (400 MHz, CDCl3) δ 4.52 (d, 4.9
Hz, 2H), 5.14 (s, 2H), 5.35 (br s, 1H), 7.35 (m, 5H), 8.42 (s, 1H),
8.85 (s, 1H), 9.34 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 41.9,
67.3, 128.1 (2C), 128.3, 128.6 (2C), 129.9, 135.8, 136.0, 143.8,
144.3, 154.0, 156.6. Anal. Calcd for C14H13N3O4: C, 58.53; H, 4.56;
N, 14.63; O, 22.28. Found: C, 58.30; H, 4.80; N, 14.42; O, 22.49.
tert-Butyl 2-(5-nitropyridin-3-yl)pyrrolidine-1-carboxylate (7b):
Conclusion
In conclusion, we have developed an efficient and reliable
strategy for the microwave-assisted preparation of flexible or
conformationally constrained amino scaffolds based on a
ꢀ-nitropyridine subunit. The approach involves the condensation
of N-carbamate R- and ꢀ-amino carbonyl derivatives with
1-methyl-3,5-dinitro-2-pyridone 1 under microwave irradiation.
The novel chemotypes thus obtained have been gathered into
three families according to morphological similarities, each
group deriving from another through one unique spatial
transformation. The three sets of compounds comprise a
homogeneous combination of endo/exocyclic nitrogen atoms and
qualify for potential bi- or tridentate binding modes. In this
study, the use of microwave technology not only impacted
reaction times and yields but also allowed us to access the core
12d, the synthesis of which was not possible under conventional
heating procedures. We have also reported unprecedented
condensations with nonsymmetrical nitrogen-containing cyclic
ketones and turned the regioselectivity issue to our advantage
to simultaneously synthesize pairs of targeted chemotypes such
as 12a/13a and 12c/13c. Further studies to broaden the scope
of this reaction are now in progress and will be reported in due
course.
1
Obtained as a light yellow solid; H NMR (400 MHz, CDCl3) δ
(mixture of rotamers) 1.33 (m, 9H), 1.94 (m 3H), 2.46 (br s, 1H),
3.76 (m, 2H), 4.98 (m, 1H), 8.28 (s, 1H), 8.78 (d, J ) 0.9 Hz, 1H),
9.30 (s, 1H); 13C NMR (100 MHz, CDCl3) δ (mixture of rotamers)
22.5, 22.8, 27.2 (3C), 27.4 (3C), 33.7, 34.8, 46.3, 46.4, 57.4, 57.7,
79.3, 127.0, 140.1, 140.9, 142.3, 143.3, 151.9, 153.0, 153.5; HRMS
calcd for C14H20N3O4 294.1454, found 294.1447.
tert-Butyl 3-nitro-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxy-
late (10b): Obtained as a yellow solid; 1H NMR (400 MHz, CDCl3)
δ (mixture of rotamers) 1.53 (s, 9H), 4.77 (m, 4H), 8.36 (m, 1H),
9.34 (s, 1H); 13C NMR (100 MHz, CDCl3) δ (mixture of rotamers)
28.2 (3C), 50.0, 50.3, 52.4, 52.7, 80.7, 125.8, 126.0, 132.0, 132.3,
143.9, 145.0, 153.0, 154.1, 164.7, 164.9. Anal. Calcd for
C12H15N3O4: C, 54.33; H, 5.70; N, 15.84; O, 24.13. Found: C, 54.33;
H, 5.74; N, 15.64; O, 23.89.
tert-Butyl 5,6-dihydro-3-nitro-1,7-naphthyridine-7(8H)-car-
boxylate (10c): Obtained as white solid; 1H NMR (400 MHz,
CDCl3) δ 1.50 (s, 9H), 2.98 (t, J ) 5.5 Hz, 2H), 3.74 (t, J ) 5.7
Hz, 2H), 4.78 (s, 2H), 8.26 (br s, 1H), 9.24 (d, J ) 1.9 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 28.1, 28.3 (3C), 48.7, 80.7, 131.1,
131.3, 142.6, 142.7, 154.4, 160.4. Anal. Calcd for C13H17N3O4: C,
55.91; H, 6.14; N, 15.04; O, 22.91. Found: C, 56.08; H, 6.34; N,
14.88; O, 22.68.
Experimental Section
Benzyl 5,6,7,8-tetrahydro-3-nitroquinolin-7-ylcarbamate (12c):
Obtained as a light yellow solid; H NMR (400 MHz, CDCl3) δ
General procedure for microwave-assisted condensation reac-
tion of 1 with various N-carbamate R- and ꢀ-amino carbonyls. A
solution of carbonyl compound (1 mmol) and 1-methyl-3,5-dinitro-
2-pyridone 1 (1.5 mmol) in methanolic ammonia (1 M, 6 mL)
was irradiated at 90 °C in a sealed vial for 20-30 min. The
mixture was then concentrated and dissolved in CH2Cl2. The
organic layer was washed with saturated aqueous NaHCO3 and
water, dried over Na2SO4, and evaporated. Depending on the
complexity of the separation, the residue was purified by chroma-
tography on normal phase (using heptane/EtOAc, 9:1) or reversed
phase silica (using H2O + 0.1% AcOH/CH3CN + 0.1% AcOH,
75:25).
tert-Butyl 2-(5-nitropyridin-2-yl)pyrrolidine-1-carboxylate (4a):
Obtained as a yellow solid; 1H NMR (400 MHz, CDCl3) δ (mixture
of rotamers) 1.21 (s, 5H), 1.45 (s, 4H), 1.97 (m, 3H), 2.40 (m,
1H), 3.60 (m, 2H), 5.00 (m, 1H), 7.39 (m, 1H), 8.42 (m, 1H), 9.36
(m, 1H); 13C NMR (100 MHz, CDCl3) δ (mixture of rotamers)
23.3, 24.0, 28.1 (3C), 28.3 (3C), 32.9, 34.2, 47.1, 47.4, 62.2, 62.7,
79.8, 119.9, 120.5, 131.3, 131.4, 142.8, 144.6, 144.7, 154.0, 154.6,
169.4, 170.5. Anal. Calcd for C14H19N3O4: C, 57.33; H, 6.53; N,
14.33; O, 21.82. Found: C, 57.33; H, 6.24; N, 14.11; O, 21.46.
tert-Butyl 2-(5-nitropyridin-2-yl)thiazolidine-3-carboxylate
(4b): Obtained as a pale yellow solid; 1H NMR (400 MHz, CDCl3)
δ (mixture of rotamers) 1.33 (m, 9H), 3.07 (m, 1H), 3.24 (br s,
1
1.82 (m, 1H), 2.18 (m, 1H), 2.89 (dd, J ) 18.1, 8.7 Hz, 1H), 2.97
(t, J ) 6.3 Hz, 2H), 3.40 (dd, J ) 18.1, 5.2 Hz, 1H), 4.13 (br s,
1H), 4.84 (br s, 1H), 5.10 (s, 2H), 7.33 (m, 5H), 8.17 (d, J ) 1.6
Hz, 1H), 9.16 (d, J ) 2.0 Hz, 1H). Anal. Calcd for C17H17N3O4: C,
62.38; H, 5.23; N, 12.84; O, 19.55. Found: C, 62.31; H, 5.58; N,
12.57; O, 19.71.
Benzyl 3,4-dihydro-7-nitro-2H-pyrano[3,2-b]pyridin-3-ylcar-
1
bamate (12d): Obtained as a white solid; H NMR (400 MHz,
CDCl3) δ 3.10 (dd, J ) 18.1, 3.5 Hz, 1H), 3.34 (dd, J ) 18.2, 5.3
Hz, 1H), 4.25 (s, 2H), 4.39 (br s, 1H), 5.02 (br s, 1H), 5.10 (s,
2H), 7.33 (m, 5H), 7.90 (d, J ) 2.0 Hz, 1H), 8.98 (d, J ) 2.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 34.9, 43.7, 67.2, 68.7, 118.6,
128.2 (2C), 128.3, 128.5 (2C), 135.8, 137.2, 143.6, 148.0, 150.3,
155.4. Anal. Calcd for C16H15N3O5: C, 58.36; H, 4.59; N, 12.76;
O, 24.29. Found: C, 58.76; H, 4.79; N, 12.53; O, 24.12.
Benzyl 6,8-dihydro-3-nitro-5H-pyrano[3,4-b]pyridin-5-ylcar-
1
bamate (13d): Obtained as a light yellow solid; H NMR (400
MHz, CDCl3) δ 3.96 (dd, J ) 11.9, 3.2 Hz, 1H), 4.07 (dd, J )
11.9, 2.9 Hz, 1H), 4.80 (d, J ) 17.4 Hz, 1H), 4.94 (d, J ) 17.4
Hz, 1H), 5.00 (m, 1H), 5.13 (d, J ) 12.3 Hz, 1H), 5.17 (d, J )
12.3 Hz, 1H), 5.38 (d, J ) 9.0 Hz, 1H), 7.35 (m, 5H), 8.61 (d, J
) 1.6 Hz, 1H), 9.29 (d, J ) 1.9 Hz, 1H); 13C NMR (100 MHz,
J. Org. Chem. Vol. 74, No. 5, 2009 1937

Henry et al.
CDCl3) δ 46.7, 67.3, 68.8, 69.8, 128.1 (2C), 128.3, 128.5 (2C),
130.9, 131.8, 135.8, 143.2, 144.1, 155.8, 160.8. Anal. Calcd for
C16H15N3O5: C, 58.36; H, 4.59; N, 12.76; O, 24.29. Found: C, 58.46;
H, 4.80; N, 12.59; O, 24.08.
Renate Kostiza, Manuela Schienemann, and Manuela Diehl for
compound purification and characterization.
Supporting Information Available: Experimental proce-
dures and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank Claudia Partos and Markus
Strubel for syntheses of carbonyl intermediates. We also
acknowledge Dr. Claudia Krack, Klaus Lang, Tina Kroenung,
JO802439D
1938 J. Org. Chem. Vol. 74, No. 5, 2009