The Kondrat'eva reaction in flow: Direct access to annulated pyridines

Article abstract of DOI:10.1021/ol4013525

A continuous flow inverse-electron-demand Kondrat'eva reaction has been developed that provides direct access to cycloalka[c]pyridines from unactivated oxazoles and cycloalkenes. Annulated pyridines obtained by this one-step process are valuable scaffolds for medicinal chemistry.

Full text of DOI:10.1021/ol4013525

ORGANIC
LETTERS
2013
Vol. 15, No. 14
3550–3553
The Kondrat’eva Reaction in Flow:
Direct Access to Annulated Pyridines
Johannes Lehmann,‡ Thibaut Alzieu,‡ Rainer E. Martin,*,‡ and Robert Britton*,†
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia,
Canada, and F. Hoffmann-La Roche AG, pRED, Pharma Research & Early
Development, Small Molecule Research, Medicinal Chemistry, Grenzacherstrasse 124,
4070 Basel, Switzerland
rbritton@sfu.ca; rainer_e.martin@roche.com
Received May 14, 2013
ABSTRACT
A continuous flow inverse-electron-demand Kondrat’eva reaction has been developed that provides direct access to cycloalka[c]pyridines from
unactivated oxazoles and cycloalkenes. Annulated pyridines obtained by this one-step process are valuable scaffolds for medicinal chemistry.
Annulated pyridines are common scaffolds in medicinal
chemistry and are present in many drug leads.1 For example,
the dihydro-5H-cyclopenta[b]pyridine 1 (Figure 1) is a low
nM agonist for the serotonin receptor 5HT2c,2 the 4-aza
analogue of ramelteon 2 is a potent melatonin receptor
agonist,3 and the naturally occurring alkaloid sinensine (3)
has demonstrated potentially useful cytoprotective activity.4
Recently, Martin et al. reported a process for the synthesis
of cycloalka[b]pyridines (e.g., 5) in continuous flow by
means of an intramolecular inverse-electron-demand hetero/
retro-DielsꢀAlder (ihDA/rDA) reaction cascade involving
pyrimidine alkynes (e.g., 4).5 To support several ongoing
drug discovery programs, access to the corresponding
cycloalka[c]pyridines, such as those constituting the struc-
tural core of alkaloids 2 and 3, was also required. In order
to efficiently sample the chemical space surrounding this
scaffold,6 we sought a concise and modular approach that
permits the incorporation of functional or diversifiable
groups on the pyridine moiety (e.g., carboxyl or haloaryl)
and provides access to annulated pyridines of differing
ring size (e.g., cyclopenta-, cyclohexa-, and cyclohepta[c]-
pyridines). As described below, these efforts led to the
development of a continuous flow inverse-electron-demand
Kondrat’eva (iedK) reaction7 that is capable of producing a
wide array of oxacycloalka- and cycloalka[c]pyridines di-
rectly from unactivated cycloalkenes and substituted oxa-
zoles. Notably, this work constitutes the first Kondrat’eva
reactions of cycloalkenes and the first examples of this
reaction in continuous flow.
‡ F. Hoffmann-La Roche AG.
† Simon Fraser University.
(1) Examples of annulated pyridine synthesis: (a) Foster, R. A.;
Willis, M. C. Chem. Soc. Rev. 2013, 42, 63. (b) Martin, R. M.; Bergman,
R. G.; Ellman, J. A. J. Org. Chem. 2012, 77, 2501. (c) Anderson, E. D.;
Boger, D. L. J. Am. Chem. Soc. 2011, 133, 12285. (d) Anderson, E. D.;
Boger, D. L. Org. Lett. 2011, 13, 2492. (e) Catozzi, N.; Edwards, M. G.;
Raw, S. A.; Wasnaire, P.; Taylor, R. J. K. J. Org. Chem. 2009, 74, 8343.
(f) Parthasarathy, K.; Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2008,
10, 325. (g) Chen, H.-W.; Hsu, R.-T.; Chang, M.-Y.; Chang, N.-C. Org.
Lett. 2006, 8, 3033. (h) Kozhevnikov, V. N.; Kozhevnikov, D. N.;
Nikitina, T. V.; Rusinov, V. L.; Chupakhin, O. N.; Zabel, M.; Koenig,
B. J. Org. Chem. 2003, 68, 2882. (i) Roesch, K. R.; Zhang, H.; Larock,
R. C. J. Org. Chem. 2001, 66, 8042. (j) Gilchrist, T.; Kemmitt, P. D.;
Germain, A. L. Tetrahedron 1995, 51, 9119. (k) Boger, D. L.; Panek, J. S.
J. Org. Chem. 1981, 46, 2179. (l) Boger, D. L.; Panek, J. S.; Meier, M. M.
J. Org. Chem. 1981, 47, 895.
The Kondrat’eva reaction7ꢀ9 involves a [4 þ 2] cycload-
dition between an oxazole (e.g., 6) and an alkene (e.g., 7),
followed by dehydration of the cycloadduct (e.g., 8)
(2) Liu, K. K.-C.; Cornelius, P.; Patterson, T. A.; Zeng, Y.; Santucci,
S.; Tomlinson, E.; Gibbons, C.; Maurer, T. S.; Marala, R.; Brown, J.;
Kong, J. X.; Lee, E.; Werner, W.; Wenzel, Z.; Vage, C. Bioorg. Med.
Chem. Lett. 2010, 20, 266.
(5) Martin, R. E.; Morawitz, F.; Kuratli, C.; Alker, A. M.; Alanine,
A. I. Eur. J. Org. Chem. 2012, 47.
(3) Koike, T.; Hoashi, Y.; Takai, T.; Uchikawa, O. Tetrahedron Lett.
2011, 52, 3009.
(4) Liu, C.; Zhao, F.; Chen, R. Y. Chin. Chem. Lett. 2010, 21, 197.
(6) Tan, D. S. Nat. Chem. Biol. 2005, 1, 74.
(7) (a) Kondrat’eva, G. Y. Khim. Nauka Prom. 1957, 2, 666. (b)
Kondrat’eva, G. Y. Izu. Akad. Nauk SSSR, Ser. Khim. 1959, 484.
r
10.1021/ol4013525
Published on Web 06/27/2013
2013 American Chemical Society

the annulated pyridines would involve a Kondrat’eva
reaction between a cycloalkene and an oxazole,12 and thus
avoid tethering of reactants, our investigations began by
exploring the microwave promoted reaction of cyclopen-
tene with 5-phenyloxazole (10) (Scheme 1). While cogni-
zant that the phenyl substituent at C5 in 10 may inhibit the
desiredreaction(videsupra) and thatcycloalkeneshavenot
demonstrated utility as dieneophiles in Kondrat’eva reac-
tions, the corresponding annulated 3-arylpyridine 15 is
an attractive scaffold for medicinal chemistry. Moreover,
conditions that promote this difficult reaction should
prove general for the synthesis cycloalka[c]pyridines.
Scheme 1. The Kondrat’eva Reaction and Microwave
Promoted Reactions of 5-Phenyloxazole with Cycloalkenes
Figure 1. Annulated pyridines in drug discovery and a contin-
uous flow process for cycloalka[b]pyridines.
to afford functionalized pyridines (e.g., 9, Scheme 1).
This reaction has been employed to great effect in the
synthesis of natural products10 and pharmaceuticals and
was classically demonstrated in the production of pyridoxine
(vitamin B6) by researchers at Merck & Co. in 1962.11
In general, the Kondrat’eva reaction is facilitated by elec-
tron-donating groups on the oxazole, with 5-alkoxy- and
5-aminooxazoles displaying similar cycloaddition reactivity
to all-carbon dienes.8f In fact, the preponderance of examples
of this reaction involve activated 5-alkoxyoxazoles.9 Con-
versely, the presence of aryl groups at oxazole positions C2 or
C5 is reported to inhibit reactions with dienophiles, possibly
due to a deconjugative effect or steric crowding in the
transition structure (e.g., 6, R1 or R3 = Ph).9h In order to
promote reactions of unactivated oxazoles (e.g., those
lacking a 5-alkoxy or 5-amino group), the reactive partners
can be tethered, in which case the cycloaddition can occur
spontaneously.10 Considering that the most direct route to
Initial attempts to effect the reaction of 5-phenyloxazole
(10) with cyclopentene (11) involved use of excess 11
(10 equiv) in o-dichlorobenzene (o-DCB) at temperatures
ranging from 120 to 210 °C in a microwave reactor13 and
provided none of the dihydro-5H-cyclopenta[c]pyridine
15. Considering the reversible nature of the [4 þ 2]-
cycloaddition, the reaction was repeated with the addition
of DBU to promote dehydration of the intermediate
cycloadduct.10e Unfortunately, these modified conditions
alsofailedtoprovidedetectablequantitiesof the annulated
pyridine 15. Finally, we explored the use of Brønsted acids
in an effort to activate the oxazole by protonation and
effect an iedK reaction.14 While very little product (<2%)
was detected with the addition of HOAc, trichloroacetic
acid, p-TsOH, or p-nitrobezoic acid, addition of either
H2SO4 or trifluoroacetic acid (TFA) led to the production
of small amounts of the annulated pyridine 15. As depicted
in Scheme 1, when 5-phenyloxazole (10) was heated with
an excess of cyclopentene and 2 equiv of TFA, yields of up
to 11% of 15 were realized. Likewise, the TFA-promoted
reaction of dihydrofuran (14) and other cycloalkenes (e.g.,
12 and 13) with 5-phenyloxazole afforded the correspond-
ing annulated pyridines 16ꢀ18 in similar yields. Despite
the fact that considerable amounts of 5-phenyloxazole
were recovered from these reactions, we were not able to
(8) For reviews that include the Kondrat’eva reaction, see: (a) Hassner,
A.; Fischer, B. Heterocycles 1993, 35, 1441. (b) Lipshutz, B. H. Chem. Rev.
1986, 86, 795. (c) Boger, D. L. Chem. Rev. 1986, 86, 781. (d) Boger, D. L.
Tetrahedron 1983, 39, 2869. (e) Turchi, I. J. Ind. Eng. Chem. Prod. Res. Dev.
1981, 20, 32. (f) Turchi, I. J.; Dewar, M. J. S. Chem. Rev. 1975, 75, 389. (g)
Karpeiskii, M. Y.; Florent’ev, V. L. Russ. Chem. Rev. 1969, 38, 540.
(9) For examples, see: (a) Jouanno, L.-A.; Tognetti, V.; Joubert, L.;
Sabot, C.; Renard, P.-Y. Org. Lett. 2013, 15, 2530. (b) Singh, V. P.;
Poon, J.-F.; Engman, L. J. Org. Chem. 2013, 78, 1478. (c) Goodman,
S. N.; Mans, D. M.; Sisko, J.; Yin, H. Org. Lett. 2012, 14, 1604. (d)
Sabot, C.; Oueis, E.; Brune, X.; Renard, P.-Y. Chem. Commun. 2012, 48,
768. (e) Lalli, C.; Bouma, M. J.; Bonne, D.; Masson, G.; Zhu, J. Chem.
Eur. J. 2011, 17, 880. (f) Janvier, P.; Sun, X.; Bienayme, H.; Zhu, J.
J. Am. Chem. Soc. 2002, 124, 2560. (g) Shimada, S.; Tojo, T. Chem.
Pharm. Bull. 1983, 31, 4247. (h) Padwa, A.; Cohen, L. A. J. Org. Chem.
1984, 49, 399.
(10) For use of intramolecular Kondrat’eva reactions in total syn-
thesis, see: (a) Chughtai, M.; Eagan, J. M.; Padwa, A. Synlett 2011, 215.
(b) Ohba, M.; Natsutani, I.; Sakuma, T. Tetrahedron 2007, 63, 10337. (c)
Ohba, M.; Izuta, R.; Shimizu, E. Tetrahedron Lett. 2000, 41, 10251. (d)
Subramanyam, C.; Noguchi, M.; Weinreb, S. M. J. Org. Chem. 1989, 54,
5580. (e) Levin, J. I.; Weinreb, S. M. J. Org. Chem. 1984, 49, 4325. (f)
Levin, J. I.; Weinreb, S. M. J. Am. Chem. Soc. 1983, 105, 1397.
(11) Harris, E. E.; Firestone, R. A.; Pfister, K.; Boettcher, R. R.;
Cross, F. J.; Currie, R. B.; Monaco, M.; Peterson, E. R.; Reuter, W.
J. Org. Chem. 1962, 27, 2705.
(13) See Supporting Information for full experimental details.
(14) Firestone, R. A.; Harris, E. E.; Reuter, W. Tetrahedron 1967,
23, 943.
(12) The cycloaddition of dihydrofuran with an activated, 5-alkoxy
oxazole in an autoclave has been reported; see: Sharif, S.; Schagen, D.;
Toney, M. D.; Limbach, H.-H. J. Am. Chem. Soc. 2007, 129, 4440.
Org. Lett., Vol. 15, No. 14, 2013
3551

improve the conversion due to high-pressure (>200 psi)
shutdown of the microwave instrument and leakage of the
volatile alkenes (e.g., bp 11 = 44ꢀ46 °C) from the crimped
(Teflon seal) vials. Bearing these complicationsin mind, we
initiated investigations of this process under flow condi-
tions,15 where high temperatures and pressures can be
more safely managed, providing a novel process space.16
As summarized in Table 1, repetition of the batch
reaction depicted in Scheme 1 between 5-phenyloxazole
(10) and cyclopentene (11) in continuous flow at 210 °C in
toluene afforded the annulated pyridine 15 in a slightly
improved yield (17%, entry 1).17 Increasing the system
pressure to 500 psi resulted in a significant increase in yield
(entry 2), while further increases in reaction pressure (e.g.,
750 psi) did not noticeably improve the process. As high-
lighted in entries 2ꢀ5, 230 °C proved to be the optimal
temperature for this reaction. Several experiments were
also conducted in an effort to minimize the amount of
cyclopentene required, as byproducts most likely formed
from the acid promoted decomposition and/or polymer-
ization of cyclopentene, and insolubility of both the start-
ing material and pyridine product in cyclopentene often
complicated the continuous flow process. Ultimately, as
indicated in entry 6, injection of a solution of the reagents
in a 1:1 mixture of tolueneꢀcyclopentene proved most
favorable. Following evaluation of several effective resi-
dence times (e.g., entries 6ꢀ8), a reaction time of 2 h in the
heated chamber provided the annulated pyridine 15 in
good yield (75%). Finally, using this optimized set of con-
tinuous flow parameters, the equivalents of TFA were
adjusted (e.g., entries 8ꢀ10), and it was found that although
very small amounts of product were produced without TFA
(<10%), increases beyond 2 equiv of TFA (e.g., 3 or 4
equiv) had little effect on the yield of 15. Thus, the reaction
conditions described in entry 8 were considered optimal for
the production of the annulated pyridine 15 and a significant
improvement over the corresponding microwave batch
reaction (Scheme 1).
Table 1. Optimization of iedK Reaction in Continuous Flowa
b
temp
tR, eff
TFA
15
(%)d
entry
(°C)
(min)
PhMe:11
psic
(equiv)
1
2
3
4
5
6
7
8
9
10
210
210
190
230
250
230
230
230
230
230
60
1:3
1:3
1:3
1:3
1:3
1:1
1:1
1:1
1:1
1:1
250
500
500
500
500
500
500
500
500
500
2
2
2
2
2
2
2
2
0
4
17
45
42
58
53
61
67
75
9
60
60
60
60
60
90
120
120
120
75
a Reaction optimization experiments were conducted on a Vaportec
R2þ/R4 flow system equipped with a high temperature 316 stainless
steel tube flow reactor (SSTFR, 10 mL) and a 250 or 500 psi back-
pressure regulator (BPR). b Effective residence time (corrected for
volume expansion, which for toluene at 210 °C is approximately
23%).5 c Pressure controlled by use of BPR. d Percent yield based on
HPLC-MS analysis with internal standard.
continuous flow process using a customized system and
flow tube reactors with slightly larger bore sizes than the
systememployed foroptimization purposes (Table 1).18ꢀ20
As highlighted in Figure 2, several cycloalkenes and com-
mercially available substituted oxazoles were combined to
rapidly prepare a small collection of annulated pyridines
15ꢀ26 in modest to good yield.21 Not surprisingly,22 the
reactions involving cyclohexene and cycloheptene (i.e.,
formation of 16 and 17) compared with cyclopentene
Having identified this optimized set of reaction condi-
tions (Table 1, entry 8), we next evaluated the scope of the
(19) The nominal, volume expansion unadjusted flow rate for a
.
reactor coil volume of 53 mL and 2 h residence time is 0.44 mL minꢀ1
However, considering the volume expansion of toluene at 210 °C is 23%,
(15) (a) Ley, S. V. Chem. Record 2012, 12, 378. (b) Wegner, J.; Ceylan,
S.; Kirschning, A. Adv. Synth. Catal. 2012, 354, 17. (c) Malet-Sanz, L.;
Susanne, F. J. Med. Chem. 2012, 55, 4062. (d) Wiles, C.; Watts, P. Chem.
Commun. 2011, 47, 6512. (e) Watts, P.; Wiles, C. Micro Reaction
Technology in Organic Synthesis; CRC Press Inc.: Boca Raton, FL, 2011.
(f) Wiles, C.; Watts, P. Future Med. Chem. 2009, 1, 1593. (g) Mason, B. P.;
Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Chem.
Rev. 2007, 107, 2300.
and at 230 °C is 26%, the corrected flow rate is 0.36 mL minꢀ1
.
(20) Typical experimental procedure: cyclopentene (10 equiv) was
added to 5-phenyloxazole (1 equiv), and the mixture was diluted with
toluene. Trifluoroacetic acid (2 equiv) was then added, and the reaction
mixture was applied to the flow coil buffered by 1 mL of a mixture of
cyclopentene (10 equiv) and trifluoroacetic acid (2 equiv) in toluene
before and after injection to mitigate diffusion. The residence time of the
reaction mixture was adjusted such that it remained in the heated area
(230 °C) for 2 h, factoring in volume expansion of the solvent (see ref 5).
The crude product was collected into a vial containing triethylamine.
The flow-coil was cooled to 100 °C and flushed with 1 column volume
(53 mL) of MeOH, which was also collected and combined with
crude product. Solvents were removed under reduced pressure, and
the crude product was purified by flash chromatography.
(21) The annulated pyridines depicted in Figure 2 proved challenging
to purify by flash chromatography due to limited solubility during
sample loading and are often partitioned between aqueous and organic
phases during reaction workup. Consequently, the isolated yields pre-
sented in Figure 2 are lower than the percentage yield calculated from
HPLC-MS analysis of the crude reaction mixtures using internal
standards.
€
(16) (a) Hessel, V.; Kralisch, D.; Kockmann, N.; Noel, T.; Wang, Q.
ChemSusChem 2013, 6, 746. (b) Hessel, V. Chem. Eng. Technol. 2009, 32,
1655.
(17) TFA is known to decompose at temp >180 °C, producing
(among other byproducts) HF, CF3H, CO2 (t1/2 at 275 °C = 15 min);
see: Jollie, D. M.; Harrison, P. G. J. Chem. Soc., Perkin Trans. 2 1997,
1571. As a precautionary measure, the products of all flow reactions
were collected directly into a flask containing triethylamine.
(18) Reactions were performed on a customized flow system consist-
ing of a Dionex P580 pump (internal pressure sensor) connected to an
oven from an HP 6890 Series GC. As a reactor coil, premium grade 304
stainless steel tubing was used (Supelco, dimensions: length ꢁ OD (ID) =
15.2 m ꢁ 3.2 mm (2.1 mm), reactor volume = 53 mL). The reactor outlet
was equipped with a small stainless-steel tube (6.6 mm bore and 100 mm
length) filled with a short silica plug and glass wool to protect the 750 psi
BPR required to keep toluene in the liquid state under superheated
conditions.
(22) (a) Sauer, J.; Wiest, H. Angew. Chem. 1962, 74, 353. (b) Feast,
W. J.; Musgrave, W. K. R.; Preston, W. E. J. Chem. Soc., Perkin Trans. 1
1972, 1527. (c) Thalhammer, F.; Wallfahrer, U.; Sauer, J. Tetrahedron
Lett. 1990, 31, 6851.
3552
Org. Lett., Vol. 15, No. 14, 2013

protocol. Finally, the iedK reaction of ethyl 4-methyl-5-
oxazolecarboxylate or ethyl 5-oxazolecarboxylate with
cyclopentene or 2,5-dihydrofuran was examined, and each
afforded the desired annulated pyridines (e.g., 24ꢀ26) in
good yield. To demonstrate the scalability of this process,
the reaction between ethyl 4-methyl-5-oxazolecarboxylate
and cyclopentene was also repeated on the 8.7 g scale and
delivered 6.9 g (60% yield) of the annulated pyridine 24.13
Notably, the total processing time for this experiment was
6.75 h, during which no increase in pressure was detected,
further indicating that there was no insoluble particle
buildup. As depicted in Figure 2, reaction of the isomeric
ethyl 5-methyl-4-oxazolecarboxylate with cyclopentene
failed to provide any of the corresponding annulated pyri-
dine 27. Notwithstanding, the annulated pyridines 15ꢀ26
produced through this one-step process represent excellent
scaffolds for medicinal chemistry.
In summary, a continuous flow inverse-electron-demand
Kondrat’eva reaction has been developed that affords
direct access to annulated pyridines and is superior to the
corresponding batch reactions. Notably, the cycloaddi-
tions of both unactivated alkenes and deactivated oxazoles
are promoted in continuous flow at elevated temperatures
and pressures (230 °C, 750 psi). Considering this reaction
provides a range of cycloalka[c]pyridines that can be
diversified or further functionalized following standard
procedures (e.g., oxidative conversion of 28 f 29),23 the
continuous flow ieK reaction is well suited for medicinal
chemistry purposes. The application of annulated pyri-
dines made readily available by this one-step process to
ongoing drug discovery programs will be reported in due
course.
Acknowledgment. This work was supported by an
NSERC Discovery Grant and Michael Smith Foundation
for Health Research Career Investigator Award to R.B.
We are very grateful to Mario Lenz, Nadja Neubauer, and
Christoph Kuratli (F. Hoffmann-La Roche AG) for tech-
nical support.
Figure 2. Continuous flow synthesis of annulated pyridines and
the oxidation of 28. a Isolated yield. b No product detected.
proceeded with much lower yields. However, each of these
annulated pyridines is prepared in a single step from
commercial materials, a significant improvement over
traditional approaches (e.g., tethering of reactants) that
limit their ready incorporation into medicinal chemistry
programs. As indicated in Figure 2, the yield of the 2,5-
dihydrofuran adduct 18 also increased considerably using
the continuous flow protocol, and several additional aryl-
substituted annulated pyridines 19ꢀ23 that possess func-
tional and diversifiable groups (e.g., cyano, bromo, chloro,
fluoro) were readily prepared following our standard
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(23) Neunhoeffer, H.; Philipp, B.; Schildhauer, B.; Eckrich, R.;
Krichbaum, U. Heterocycles 1993, 35, 1089.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 14, 2013
3553