Ruthenium-catalyzed cycloisomerization-6π-cyclization: A novel route to pyridines

Article abstract of DOI:10.1021/ol070163t

Equation presented Herein we report a method for the synthesis of substituted pyridines. The unsaturated ketones and aldehydes derived from the cycloisomerization of primary and secondary propargyl diynols in the presence of [CpRu (CH₃CN)₃

Full text of DOI:10.1021/ol070163t

ORGANIC
LETTERS
2007
Vol. 9, No. 8
1473-1476
Ruthenium-Catalyzed
Cycloisomerization−6π-Cyclization:
A Novel Route to Pyridines
Barry M. Trost* and Alicia C. Gutierrez
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
bmtrost@stanford.edu
Received January 22, 2007
ABSTRACT
Herein we report a method for the synthesis of substituted pyridines. The unsaturated ketones and aldehydes derived from the cycloisomerization
of primary and secondary propargyl diynols in the presence of [CpRu(CH3CN)3]PF6 (1) are converted to 1-azatrienes which in turn undergo a
subsequent electrocyclization−dehydration to provide pyridines with excellent regiocontrol.
Functionalized pyridines have a range of applications in
many areas of chemistry.1 Not surprisingly, a large amount
of work has been devoted to the development of methods to
provide these products in a straightforward fashion.2,3 New
strategies for stiching together pyridines therefore can
enhance the flexibility of approaching these important
structural entities. The elegant transition metal-catalyzed
[2+2+2] cycloaddition of a tethered diyne and a substituted
nitrile is one such approach (eq 1).4 While recent catalytic
presence of [CpRu(CH3CN)3]PF6 (1) has been demonstrated
(eq 2).7 This method quickly builds molecular complexity
from readily available starting materials. The following
general reaction was proposed as an alternative to the
intramolecular aldol condensation.8
In an effort to highlight the utility of the ruthenium-
catalyzed cycloisomerization, its application in the synthesis
of substituted heterocycles was examined. Specifically, it was
anticipated that the dienal or dienone formed from the cyclo-
isomerization reaction could be converted to azatriene 4,
which, after 6π-cyclization, would afford intermediate di-
hydropyridine 5. This intermediate would then eliminate water
to form pyridine 6 (Scheme 1). While the electrocyclic ring
methods achieve high levels of regioselectivity for certain
classes of substrates (e.g., substrates with two sterically
differentiable substituents), the question of regioselectivity
remains ambiguous.5,6
Recently, the cycloisomerization of diynols of type 2 to
form R,â,γ,δ-unsaturated ketones and aldehydes in the
(1) Joule, J. A.; Mills, K. In Heterocyclic Chemistry, 4th ed.; Black-
well: Oxford, UK, 2000.
(5) Louie, J.; Zuo, G.; Doung, H. A.; McCormick, M. J. Am. Chem.
Soc. 2005, 127, 5030-5031.
(2) Jones, G. Pyridines and their benzoderivatives: synthesis. In Com-
prehensiVe Heterocyclic Chemistry II; Katritzky, A., Rees, C.W., Scriven,
E. F., Eds.; Pergamon: Oxford, England, 1996; Vol. 5, p 167.
(3) For a recent example, see: Movassaghi, M.; Hill, M. D. J. Am. Chem.
Soc. 2006, 128, 4592-4593.
(6) Yamamoto, Y.; Kinpara, K.; Ogawa, R.; Nishiyama, H.; Itoh, K.
Chem. Eur. J. 2006, 12, 5618-5631.
(7) (a) Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2002, 124, 4178-
4179. (b) Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2005, 127, 4763-
4776.
(4) Saa, C.; Varela, J. Chem. ReV. 2003, 103, 3787-3801.
(8) Wolinsky, J.; Baker, W. J. Am. Chem. Soc. 1960, 82, 636-638.
10.1021/ol070163t CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/16/2007

Scheme 1. Pyridine Formation via Dehydrative Cyclization of
Scheme 3. Initial Studies: Ru-Catalyzed
Cycloisomerization-6π-Cyclization Conditions
Azatriene
closure of 1,3,5-hexatrienes is widely known, there are only
two reports of the analogous electrocyclization of 1-azatrienes
to form simple, nonfused pyridine products.9 If successful,
this method could be used to construct substituted pyridines
with excellent regiocontrol, obviating the problems encoun-
tered in the metal-catalyzed [2+2+2] cycloaddtion systems.
To examine the proposed reaction sequence, diynol 2a was
prepared, and, upon exposure to catalyst 1, afforded the
desired aldehyde (3a).7 Treatment of 3a with hydroxylamine
hydrochloride and sodium acetate in refluxing ethanol
provided azatriene 4a (Scheme 2). Unfortunately, when 4a
in 70% yield, which upon heating with hydroxylamine
hydrochloride and sodium acetate in ethanol afforded pyri-
dine 6b directly. Oxime 4b presumably forms under these
conditions, and spontaneously undergoes the dehydrative
cycloisomerization
In view of the enhanced reactivity of 4b, we decided to
develop general conditions for a one-pot pyridine synthesis
from the R,â,γ,δ unsaturated aldehydes. The reaction to form
pyridine 6b took 24 h at 90 °C (Table 1, entry 1), and when
Table 1. Conditions for Pyridine Formation from Dienal 3be
Scheme 2. Construction of Dienal Substrate by Ru-Catalyzed
Cycloisomerization and Conditions for Formation of Pyridine
time
(h)
temp
(°C)
yield of
6b (%)
entry
R
conditions
NAoaC
NaOAc sealed tube
NaOAc microwave
1
2
3
4
5a
H
H
H
24
4
1
1
0.5
90
150
150
150
0-25
80
82
98
68
b
Me NaOAc, microwave
pyridine then AcCl
H
a Pyridine used as solvent. b Acetoxy derivative of 4b isolated as the
only product in 69% yield.
the temperature was raised to 150 °C, the reaction was
complete in 4 h (Table 1, entry 2). Futhermore, when the
same reaction was run under microwave irradiation, it was
complete in only 1 h, affording the desired pyridine in 98%
yield (Table 1, entry 3). The effect of the nitrogen substituent
(hydroxy versus methoxy) substitution was also examined.
The yield dropped to 68% when methoxyamine hydrochlo-
ride was used (Table 1, entry 4).
Katsumura described the formation of pyridines from
N-acetoxy azatrienes at room temperature.9b The substrates
examined were limited to those with both a C4-carbonyl
group and C6-alkenyl group. In the investigation of pyridine
formation from dienal 3b, the 6π-electrocyclization did not
proceed under similar conditions (Table 1, entry 5). Reaction
did occur at elevated temperatures (>100 °C), but was
plagued with impurities formed from undesired side reac-
tions.
was refluxed in toluene for 24 h, no cyclized material was
observed. When subjected to microwave10 irradiation, how-
ever, cyclization proceeded efficiently. Ultimately, the
desired pyridine (6a) was accessed in 95% yield over two
steps from aldehyde 3a.
Encouraged by this positive result, the aryl-substituted
diynol 2b was employed to optimize the reaction (Scheme
3). Cycloisomerization of diynol 2b provided aldehyde 3b
(9) (a) Schiess, P.; Chia, H.; Ringele, P. Tetrahedron Lett. 1972, 313.
(b) Tanaka, K.; Mori, H.; Yamamoto, M.; Katsumura, S. J. Org. Chem.
2001, 66, 3099-3110.
(10) It has been shown that microwave irradiation can provide key
advantages over conventional thermal methods, especially in cases when
usual methods require forcing conditions or prolonged reaction times.
Besson, T.; Brain, C.; Westman, J. In MicrowaVe Assisted Organic
Synthesis; Tierney, J. P., Lidstrom, P., Eds.; Blackwell Publishing: Oxford,
UK, 2005; Chapters 3 and 5.
1474
Org. Lett., Vol. 9, No. 8, 2007

Having identified conditions suitable for the one-step
conversion of dienals to pyridines, efforts to determine the
scope of this synthetic methodology were undertaken. Thus,
a variety of diynol substrates of type 2 were constructed,
and the cycloisomerization-6π-cyclization sequence applied
(eq 3).
Table 2. Pyridines via the
Cycloisomerization-6π-Electrocyclization Sequence
The use of alkynes linked by heteroatoms was of particular
interest, as they can be potentially cleaved at a later stage,
allowing for further functionalization of the pyridine skeleton
at the 3 and 4 positions. We found that heteroatoms are
indeed tolerated (Table 2, entries 3, 4, and 5). The reactivity
of substrates without R-branching at the propargylic position
(R2 ) Me, Et) was also demonstrated (Table 2, entries 7-9).
As part of our effort to explore the scope of the cycloi-
somerization-6π-cyclization sequence, an examination of
the effect of ring size was undertaken. Tethers which
cycloisomerize to form 6-membered rings have been shown
to give slightly lower yields in the ruthenium-catalyzed
cycloisomerization than those which form 5-membered
rings.7 We were pleased to find that 2f (Table 1, entry 6)
underwent the cycloisomerization-6π-cyclization, in high
yield for both steps.
Previously, the only isolable products from the cyclization
of secondary propargylic alcohols had the E-olefin config-
uration at the γ,δ-double bond. It was postulated that
elimination of the hyroxyl group may occur stereoselectively,
where the observed E/Z ratio is dictated by steric interactions
between the R2 group and the cyclopentane ring.7 In a
number of the substrates examined, we observed for the first
time products containing the external olefin in a mixture of
E- and Z-olefin geometries. In some of the examples explored
herein the differential A-1,3 strain between the olefin
substituent and the annealed ring vs the ligands on Ru appear
to be more competitive because of olefin’s smaller size. The
6π-cyclizations of these substrates proceeded with complete
consumption of starting material (Table 2, entries 5-9), the
double bond mixtures having no noticeable effect on the yield
of the pyridine obtained in the subsequent 6π-cyclization.
Ketones are known to generate oximes as a mixture of
isomers, and we wondered whether this mixture would
impact the 6π-cycloisomerization reaction.11 Internal diynols
2d, 2e, 2i, and 2j were prepared and submitted to the
cycloisomerization reaction to give the desired ketones in
high yields (Table 2, entries 4, 5, 9, and 10). The formation
of pyridines from dienones 3d, 3e, and 3i took place readily,
forming the corresponding pyridines 6d, 6e, and 6i in good
yields. With use of the conditions of Table 1, entry 2, the
reaction of dienone 3j required higher temperatures and
longer times to provide the corresponding pyridine 6j, in a
reduced yield of 67%. The best yields of 6j were obtained
when the azatriene was first isolated, and then submitted to
the 6π-cyclization in trifluorotoluene, in which case an 85%
yield was obtained (Table 2, entry 10).
a See ref 7. b Methods: (i) NH2OH‚HCl, NaOAc, EtOH, 90 °C, 30 min,
(ii) PhCF3, microwave, 220-240 °C, 4 h. c Method: NH2OH‚HCl, NaOAc,
EtOH, microwave, 150 °C, 1-1.5 h. d Method: NH2OH‚HCl, NaOAc,
EtOH, 90 °C, 5-24 h. e E ) CO2Me.
(11) If one considers the disrotatory model for thermal 6π-electrocy-
clizations, only the E-isomer would position the hydrogen and the
N-hydroxyl group which are to be eliminated trans (anti-periplanar) to each
other in the resulting dihydropyridine. The Z-isomer might also introduce
steric strain that would prevent the substituents from attaining the required
planar confirmation.
We also examined substrates containing a terminal olefin
(Table 2, entry 4). As reported previously, primary alcohols
cycloisomerize to yield both the expected cycloisomerized
product 3d and the formally hydrated product 7. When dienal
Org. Lett., Vol. 9, No. 8, 2007
1475

3d was subjected to our one-step pyridine syntheses com-
pound 6d formed in good yield (Scheme 4).
Scheme 5. Conditions for One-Pot Protocol
Scheme 4. Behavior of Primary Propargyl Alcohols
Finally, to increase the utility of this methodology, we
sought to access the pyridine directly from the diynol (2) in
a one-pot protocol. Acetone, which is the preferred solvent
for the cycloisomerization, poses problems for the reaction
with hydroxylamine. This problem could be circumvented,
however, by first performing the initial cycloisomerization
with our standard conditions (acetone/water). Upon comple-
tion, the solvent could be removed, and the crude residue
subjected to the previously mentioned pyridine-forming
conditions. This mixture was heated in the microwave to
afford pyridine 6e in 54% yield (Scheme 5).
In conclusion, the method we report here represents a facile
route to pyridines that demontrates the utility of the
ruthenium-catalyzed cycloisomerization reaction. The reac-
tion sequence tolerates a broad range of functional groups.
The double-bond isomeric mixture obtained from the cy-
cloisomerization reaction did not have an effect on the yield
of the subsequent electrocyclization. The cycloisomeriza-
tion-6π-cyclization sequence may be carried out in one pot
or in two independent steps. Additionally, the azatriene
cyclization may be carried out in 1-3 h under microwave
irradiation or, for more sensitive substrates, at lower tem-
peratures for longer periods of time (6-24 h at 90 °C). All
of the substrates examined underwent the 6π-cyclization to
the corresponding pyridines under a variety of conditions
and in excellent yields. Our current efforts are directed at
improvement of the one-pot protocol and application of this
methodology to the synthesis of biologically significant
natural products.
Acknowledgment. We thank the National Science Foun-
dation and the National Institutes of Health, General Medical
Sciences Institute (GM-13598), for their generous support
of our programs. We also thank Biotage Inc. for providing
the microwave reactor and continuing to provide invaluable
help with its service. Mass spectra were provided by the Mass
Spectrometry Facility of the University of California-San
Francisco, supported by NIH Division of Research Re-
sources.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL070163T
1476
Org. Lett., Vol. 9, No. 8, 2007