Cyclopenta[b]pyrroles from triazines: synthetic and mechanistic studies

Article abstract of DOI:10.1021/ol902559u

"Chemical Equation Presented" The pyrrolidine-mediated reactions of 3,5-disubstituted 1,2,4-triazines with cyclobutanone lead to cyclopenta[b]pyrroles, which can be derivatized into hydrazones and oximes. The cyclopenta[b]pyrrole ring system likely arises through a tandem [4 + 2] cycloaddition/cycloreversion/ring rearrangement reaction. In contrast, 3,6-disubstituted 1,2,4-triazines undergo a simple nucleophilic 1,4-addition with cyclobutanone to give 1:1 adducts.

Full text of DOI:10.1021/ol902559u

ORGANIC
LETTERS
2010
Vol. 12, No. 1
164-167
Cyclopenta[b]pyrroles from Triazines:
Synthetic and Mechanistic Studies†
Long Ye,‡ Makhluf J. Haddadin,§ Michael W. Lodewyk,‡ Andrew J. Ferreira,‡
James C. Fettinger,‡ Dean J. Tantillo,‡ and Mark J. Kurth*,‡
Department of Chemistry, UniVersity of California, One Shields AVenue,
DaVis, California 95616, and Department of Chemistry, American UniVersity of
Beirut, Lebanon
mjkurth@ucdaVis.edu
Received November 5, 2009
ABSTRACT
The pyrrolidine-mediated reactions of 3,5-disubstituted 1,2,4-triazines with cyclobutanone lead to cyclopenta[b]pyrroles, which can be derivatized
into hydrazones and oximes. The cyclopenta[b]pyrrole ring system likely arises through a tandem [4 + 2] cycloaddition/cycloreversion/ring
rearrangement reaction. In contrast, 3,6-disubstituted 1,2,4-triazines undergo a simple nucleophilic 1,4-addition with cyclobutanone to give 1:1
adducts.
An important synthetic application of substituted 1,2,4-
triazines is their reaction as azadienes in inverse electron
demand Diels-Alder reactions to generate substituted py-
ridines.1,2 Analogously, 1,2,4,5-tetrazines are known to react
with electron-rich enes to give substituted pyridazines.3
However, in previous work from our laboratory, we did not
obtain the expected pyridazine derivative 5 by the reaction
of tetrazine 3 with cyclobutanone enolate 2.4-6 Rather,
instead of intermediate 4 eliminating water to aromatize
(f 5), diazocinone 6 was obtained through a ring-expansion
reaction (Scheme 1).4,5
Attempts to extend this reaction to produce an eight-
membered heterocycle containing a sulfur and two nitrogen
atoms by reacting 3 with thietanone 7 and base (Scheme 1)
† Dedicated to Professor Jeremiah P. Freeman on the occasion of his
80th birthday and for his excellent service to Organic Syntheses.
‡ University of California, Davis.
§ American University of Beirut.
(1) For reviews of inverse electron-demand Diels-Alder reactions using
azadienes, see: (a) Boger, D. L. Tetrahedron 1983, 39, 2869. (b) Boger,
D. L. Chem. ReV. 1986, 86, 781. (c) Boger, D. L.; Weinreb, S. N. Hetero
Diels-Alder Methodology in Organic Synthesis; Academic Press: New York,
1987; Organic Chemistry Monograph Series, Vol. 47. (d) Kametani, T.;
Hibino, S. In AdVances in Heterocyclic chemistry; Katritzky, A. R., Ed.;
(3) (a) Sakya, S. M.; Groskopf, K. K.; Boger, D. L. Tetrahedron Lett.
1997, 38, 3805. (b) Saracoglu, N. Tetrahedron 2007, 63, 4199. (c) Geyelin,
P. H.; Raw, S. A.; Taylor, R. J. K. ArkiVoc 2007, 37.
Academic Press: New York, 1987; Vol. 42, p 246
.
(4) (a) Haddadin, M. J.; Agha, B. J.; Salka, M. S. Tetrahedron Lett.
1984, 25, 2577. (b) Robins, L. I.; Carpenter, R. D.; Fettinger, J. C.;
(2) (a) Boger, D. L.; Panek, J. S.; Yasuda, M. Org. Synth. 1993, 8, 597.
(b) Sainz, Y. F.; Raw, S. A.; Taylor, R. J. K. J. Org. Chem. 2005, 70,
10086. (c) Benson, S. C.; Gross, J. L.; Snyder, J. K. J. Org. Chem. 1990,
55, 3257. (d) Ernd, M.; Heuschmann, M.; Zipse, H. HelV. Chim. Acta 2005,
88, 1491. (e) Carroll, F. I.; Kotturi, S. V.; Navarro, H. A.; Mascarella, S. W.;
Gilmour, B. P.; Smith, F. L.; Gabra, B. H.; Dewey, W. L. J. Med. Chem.
Haddadin, M. J.; Tinti, D. S.; Kurth, M. J. J. Org. Chem. 2006, 71, 2480
.
(5) Lodewyk, M. W.; Kurth, M. J.; Tantillo, D. J. J. Org. Chem. 2009,
74, 4801
.
(6) (a) Suen, Y. F.; Hope, H.; Nantz, M. H.; Haddadin, M. J.; Kurth,
M. J. Tetrahedron Lett. 2006, 47, 7893. (b) Suen, Y. F.; Hope, H.; Nantz,
2007, 50, 3388
.
M. H.; Haddadin, M. J.; Kurth, M. J. J. Org. Chem. 2005, 70, 8468.
10.1021/ol902559u  2010 American Chemical Society
Published on Web 12/04/2009

disubstituted 1,2,4-triazines (9) with cyclobutanone. Upon
addition of 9a to a mixture of cyclobutanone and pyrrolidine,
nitrogen extrusion occurred as evidenced by the formation
of gas bubbles.7 Analysis of the reaction mixture by mass
spectrometry indicated the presence of components with [M
+ H+] ) 277 and 330, which could correspond to the eight-
membered ring system 12 (X ) O- and N-pyrrolidine,
respectively). Attempted purification of the crude mixture
on a silica or alumina column led only to decomposition. In
anticipation of the potential ketone functionality that would
result from tautomerization of the desired azocine 12 (X )
OH), the crude product mixture was reacted with (Br-
Ph)NHNH2·HCl (or BnONH2·HCl) in the hope that a more
stable hydrazone (or oxime) of ring-expanded azocine 12
could be isolated and characterized.8 We were surprised to
discover that, instead of obtaining the anticipated hydrazone
or oxime of 12, hydrazone 16a and oxime 16b derivatives
of the cyclopenta[b]pyrrole ring system 15 were formed.
Establishing the structure of 16 was challenging. Efforts
to obtain X-ray quality crystals of hydrazone 16a were
unsuccessful under a variety of conditions. 1H NMR spectra
of 16a and 16b indicated the presence of seven aliphatic
protons, which excluded the possibility of 12. Analysis of
the HSQC and COSY spectra of 16a and 16b indicated the
connectivity of the three CH2 and CH groups in the bicyclic
structure of 16. The final cyclopenta[b]pyrrole structure was
Scheme 1
.
Tetrazine-Based Reaction Cascades Leading to
Diazocinone 6 and Pyrazole 8
led to substituted pyrazole 8.6 In light of our results in
Scheme 1 as well as the report by Taylor et al. that triazine
9a (Scheme 2) undergoes an inverse electron demand
1
arrived at by analyzing the H-13C long-range coupling
Scheme 2
.
Mechanistic Possibilities for Formation of
Cyclopenta[b]pyrrole Derivatives
peaks in the HMBC spectra of 16 (see Supporting Informa-
tion). The results of 1H NMR calculations at the B3LYP/6-
311+G(2d,p)//B3LYP/6-31G(d) level are consistent with
assignment of a cis rather than a trans configuration for 16
(see Supporting Information for details). Finally, we were
able to obtain X-ray quality crystals of the (E)-oxime 16d,
and to our delight, the resulting crystal structure (Figure 1)
Figure 1. X-ray structure of the (E)-isomer of oxime 16d.
confirmed our NMR-derived structural and stereochemical
assignments (see Supporting Information for the crystal
structures of both (E)-16d and (Z)-16d).
(7) Dry chloroform (1 mL) and 3 Å molecular sieves were added to a
mixture of pyrrolidine (22 µL, 0.26 mmol) and cyclobutanone (320 µL,
4.3 mmol) in a sealable thick-wall test tube. Triazine 9a (200 mg, 0.86
mmol) was then added to the above solution after it was stirred for 10 min.
After bubbling stopped, the tube was sealed, and the reaction was stirred at
60 °C for 3-5 h and monitored by LC/MS.
Diels-Alder reaction with the pyrrolidine enamine of
cyclopentanone,2b we investigated the reaction of 3,5-
Org. Lett., Vol. 12, No. 1, 2010
165

We also wondered if 3,6-disubstituted 1,2,4-triazine (17)
would react with enolate 2 to give a cyclopenta[b]pyrrole
(e.g., 18; pathway A, Scheme 3) or an azocinone (e.g., 19;
Intrigued by the unexpected formation of cyclopenta[b]-
pyrrole analogues 16a and 16b (Scheme 2), we set out to
examine the possible mechanisms by which these products
are formed. The first question regards the role of pyrrolidine.
One possibility is that this amine reacts with cyclobutanone
to form the corresponding enamine (2′ in Scheme 2). This
species could then participate as an electron-rich dienophile
in a cycloaddition with triazine 9 to form intermediate 10
and, by loss of N2, 11 (X ) N-pyrrolidinyl).10 This scenario
is supported by Taylor’s observation of 22 in a closely related
reaction.2b Alternatively, pyrrolidine may simply function
as a base and form small quantities of enolate 2 (protonated
pyrrolidine is more acidic than cyclobutanone by ∼10 pKa
units), which through reaction with 9 would give 11 (X )
O-). Previously 2, generated using KOH/methanol, was
shown to react in a similar manner with a 1,2,4,5-tetra-
zene.4-6 In fact, employing KOH/methanol, while not
effective in preparative reactions, does result in the reaction
of cyclobutanone with 9 to give 12 (X ) OH) and/or 15 as
evidenced by LC/MS of the crude reaction mixture. However,
no reaction was observed when DBU was used as base.
Scheme 3. Reactions of 3,6-Disubstituted 1,2,4-Triazines
pathway B, Scheme 3). Analysis of the reaction mixture from
1,2,4-triazine 17a by LC/MS revealed that unreacted starting
material was a major component in the mixture, accompanied
by a trace amount of what appeared to be an addition product
according to its molecular ion ([M + H+] ) 304). However,
when a 1,2,4-triazine with an electron-withdrawing 2-pyridyl
at the C3 position (17b) was reacted with cyclobutanone
enolate 2, a mixture of tautomeric adducts 20 and 20′ resulted
(pathway C, Scheme 3). The tautomeric nature of these
addition products is evidenced by two sets of doublets (Ha,
5.43 and 5.35 ppm) and two sets of broad singlets (Hb, 10.21
Whether intermediate 11 is formed with X ) O- or X )
N-pyrrolidinyl, there are at least two possible paths by which
it can be converted to 15. As depicted in Scheme 2, 11 may
undergo a substituent-accelerated six-electron, electrocyclic
ring-opening reaction to form the eight-membered system
12,5 which could then contract into 14. Alternatively, a direct
1,2-alkyl shift may occur, as predicted previously for related
systems,5 to produce 13, a tautomer of 15. In order to gain
additional insight into these possibilities, density functional
theory calculations (B3LYP/6-31+G(d,p); see Supporting
Information for details) were employed to probe the key steps
outlined in Scheme 2. As shown in Figure 2 (see Supporting
Information for additional structures), transition state struc-
tures corresponding to the 11 f 12 f 14 pathway for species
derived from both 2 and 2′ were located. However, transition
state structures for direct 1,2-alkyl shifts for either the
enamine or enolate systems could not be located.11 These
observations lead us to conclude that the reaction likely
occurs via a stepwise ring-opening/ ring-closing sequence.12
Our calculations suggest that the enolate version of 12 would
face lower barriers to form 14 than would the enamine
version (Figure 2). On balance, although neither the enolate
nor enamine pathways can be definitively ruled out, we favor
the enolate mechanism.
1
and 10.06 ppm) in the H NMR of these isolated products
as well as their co-eluting LC/MS peak with [M + H+] )
305. Indeed, nucleophilic addition to 17b is precedented.9
An analogous addition product was observed upon reaction
of thietanone 7 with triazine 17b in the presence of KOH
(Scheme 3). Adduct 21 was fully charaterized by 1H NMR,
13C NMR, LC/MS, and X-ray crystallography (see Support-
ing Information). When LHMDS was used as base instead
of KOH, the yield of 21 increased from 36% to 50%;
presumably because the non-nucleophilic LHMDS is less
likely to add to 17b.
(8) After the relative amount of triazine starting material no longer
decreased as indicated by LC/MS, the reaction mixture was cooled to room
temperature and concentrated under reduced pressure. The crude product
was redissolved in ethanol and mixed with hydrazine or O-Bn hydroxyamine
hydrochloride in a 90% ethanol/10% water solution. This mixture was
refluxed for 2 h, the solvent was then removed, and the crude product was
dried in DCM over Na2SO4, followed by chromatographic purification (silica
gel with gradient hexane/ethyl acetate elution).
(10) On the basis of calculations on a related system, it is possible that
10 is not a true minimum on the potential energy surface for this reaction.5
(11) Note here that additional calculations (see Supporting Information)
revealed that structure 15 (X ) O) is at least 20 kcal/mol lower in energy
than neutral tautomers of structure 12.
(9) Konno, S.; Ohba, S.; Sagi, M.; Yamanka, M. Chem. Pharm. Bull.
1987, 35, 1378.
(12) See Supporting Information for discussion related to this same
possibility for the tetrazine-derived systems studied in ref 5.
166
Org. Lett., Vol. 12, No. 1, 2010

Table 1. Examples of Tandem Cycloaddition and Ring
Rearrangement (9 f 16)
entry code
R1
R2
R3
yielda
1
2
3
4
5
16a
16b
16c
16d
16e
2-pyridyl Ph
2-pyridyl Ph
2-pyridyl naphthenyl BnO
2-pyridyl (p-Br)Ph
EtOC(O) Ph
NHPh(p-Br)
BnO
50
48
42
44b
38
BnO
BnO
a Percent isolated yield. b Including both E- and Z-oxime isomers.
phenyl-1,2,4-triazine and 3-(methylsulfonyl)-5-phenyl-1,2,4-
triazine. The former did not react, and the latter resulted in
a complex product mixture.
In summary, we have demonstrated that cyclopenta[b]-
pyrroles 16 can be formed via a one-pot, tandem cycload-
dition/cycloreversion/ring rearrangement reaction starting
from 3,5-disubstituted 1,2,4-triazines and cyclobutanone.
Figure 2. Computed transition state structures (selected distances
shown in angstroms).
Acknowledgment. We thank the National Science Foun-
dation (CHE-0910870 and CHE-0449845) for generous
financial support, Professor Hakon Hope (Department of
Chemistry, University of California, Davis) for suggestions
on crystallization, and John M. Knapp (Department of
Chemistry, University of California, Davis) for laboratory
assistance.
Encouraged by these observations and the definitive
identification of 16a and 16b, we carried out the tandem
cycloaddition and ring rearrangement reaction on a short
series of 1,2,4-triazines (Table 1). We found that an electron-
withdrawing group at R1 is required to form the cyclopent-
a[b]pyrrole ring system. Pyridyl and ester groups at R1 enable
this reaction, with the ester analogue reacting faster than the
pyridyl analogue. The moderate to low yields observed can
be attributed to an incomplete cascade reaction, rather than
inefficient hydrazone or oxime formation, and the relative
instability of 15 under basic conditions as evidenced by LC/
MS analysis of crude product mixtures. Although hydrazone
and oxime formation proceed in comparable yields (Table
1, entry 1 vs entry 2), we focused on the formation of oximes
because of their better solution stability. Two additional
triazines were employed in this reaction: 3-(methylthio)-5-
Supporting Information Available: Full experimental
details, characterization data (1H NMR, 13C NMR, LC/MS,
and HRMS) for all new compounds, 2D NMR data for 16a
and 16b, crystallography data (CIF files) for (E)-16d, (Z)-
16d, and 21, and details on quantum chemical calculations.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL902559U
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