Double cyclization via intramolecular coupling between cyclohexadiene-Fe(Co)3 complexes and pendant conjugated dienes

Article abstract of DOI:10.1021/ja0210188

Intramolecular double cyclization between a cyclohexadiene-Fe(CO)₃ complex and a pendant diene yielded a tricyclic molecule containing a spirocenter, with defined relative stereochemistry of four contiguous carbon centers. The nature of the sub

Full text of DOI:10.1021/ja0210188

Published on Web 12/21/2002
Double Cyclization via Intramolecular Coupling between
Cyclohexadiene-Fe(CO)3 Complexes and Pendant Conjugated Dienes
Anthony J. Pearson* and Xiaolong Wang
Department of Chemistry, Case Western ReserVe UniVersity, CleVeland, Ohio 44106
Received July 25, 2002 ; E-mail: ajp4@po.cwru.edu
Table 1. Cyclization of Amide Complexes 2
The diene-Fe(CO)3 moiety has been widely used for stereose-
lective construction of C-C bonds,1 especially for the formation
of quaternary carbon centers in synthesis.2 Synthesis of spirocyclic
and angularly fused tricyclic systems, which have such quaternary
centers embedded in their molecular structures, is an area of much
interest in terms of the presence of these frameworks in many
naturally occurring compounds.3 An interesting intramolecular
coupling between a cyclohexadiene-Fe(CO)3 complex and a
pendant olefin to generate spirocycles was introduced by our group.4
The best substrates for this reaction are amide complexes, which
are converted to spirolactams (eq 1).
c
timea
(h)
concentration
(mol/L)b
yield 4
(%)
1
2
reactant
R , R
product
2a
2b
2c
2d
H, Me
OMe, Me
H, CO2Me
OCH3, CO2Me
10
24
12
24
4a
4b
4c
4d
0.02
75
54
51
34
0.004
0.004
0.004
One of the problems with this reaction is that it produces a pair
of epimers as a result of thermal rearrangement of the diene-Fe-
(CO)3 system that involves a hydride migration.4,5 Although
introducing a cyano or phenyl group at C(5) can control the diene
regiochemistry, it brings in several restrictions4a and makes the
reaction difficult for practical use in synthesis.
a Reaction time for cyclization step. b Concentration of reactant 2.
c Overall yield from 2 after demetalation, two steps.
With our continuing development of synthetic organoiron
chemistry, we report here a double cyclization reaction which avoids
epimerization of the product and gives a single diastereomerically
pure tricyclic product. The whole process is similar to two
successive ene-type reactions.
The stereochemistry of 3a was determined by 2D COSY and
2D NOESY experiments. There was strong NOE between H3a and
H9, but no effect between H3a and H5 or H3a and H5a, which
indicated the stereochemical relationship between each of the latter
pairs is trans. Strong NOE was also observed between H3a and H11,
H11′, which showed the cis relationship between H3a and 5-ethyl
and confirmed the trans relationship between H3a and H5. The
structure was also supported by the coupling constant between H5
and H5a (J ) 8.4 Hz).
The proposed mechanism, which is based on the above results
and our previous work,4 is shown in Scheme 1. Under thermal
conditions, dissociation of one CO ligand from complex 2a creates
a vacant coordination site, which is then occupied by one of the
double bonds from the pendant diene (6). Cyclization (reductive
elimination) leads to metallacycle 7. The newly formed C(3a)-
C(10) bond is syn to the metal, and the stability of the metallacycle
fixes the configuration of C(3a).4a Hydride migration and reductive
The substrates (2) for the cyclization were readily prepared in
high yield from carboxylic acid complexes4b,6 (1) (eq 2). Refluxing
2a in anhydrous di-n-butyl ether (0.02 mol/L) under carbon
monoxide atmosphere for 10 h yielded a single diene-Fe(CO)3
complex 3a in 75% yield (Table 1). No other diastereomers were
1
detected by H NMR of the reaction mixture. The only detected
side products appear to be isomers of the starting material (<2%
yield). Demetalation of 3a using trimethylamine N-oxide in benzene
produced 4a smoothly in almost quantitative yield.
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10.1021/ja0210188 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
complexes.8 We therefore decided to add an ester group to the
pendant diene system, hoping that it would facilitate the reaction
and improve the yield. Unfortunately cyclization of 2c and 2d
seemed to suffer from side reactions of the labile dienoate. High
dilution of reactants is required; 4c and 4d were formed in 51%
and 34% yields, respectively (Table 1).
Scheme 1. Proposed Mechanism
Hydrolysis of methoxycyclohexadiene 4b (oxalic acid, water and
methanol)6 and 4d (MeSiCl3, CD3CN, then water)9 gave enone 13
in 75% yield and 14 in 68% yield (eq 3), which are expected to be
more useful than the aforementioned diene for further functional-
ization.
In conclusion, intramolecular double cyclization between a
diene-Fe(CO)3 complex and pendant diene provides a complex
tricyclic molecule containing four contiguous chiral carbon centers,
with excellent stereocontrol from relatively simple and easily
available starting material. Similar structures are present in con-
imine, conamine and conessine.3d,10 The scope, application, and
enantioselectivity of this reaction are currently under investigation.
elimination delivers 16e intermediate 8. Formation of 9 and 9′ (see
later) could occur by addition of a CO ligand or rearrangement of
the diene-Fe(CO)3 system. Further coordination of 8 with the
remaining double bond and subsequent second cyclization produces
11. Again, the newly formed C(5)-C(5a) bond is endo to the metal,
and C(5) stereochemistry is controlled by the metal just as for that
at C(3a). Hydride migration, reductive elimination, and coordination
of CO ligand yields the final product 3a. Since H(5a) is exo to the
Fe(CO)3 group, hydride migration to C(9) is prevented.5
Acknowledgment. We thank the National Science Foundation
for financial support (CHE-0131043).
Supporting Information Available: Experimental procedures and
Figures giving NMR spectra (1H, 13C) of all new compounds, 2D
COSY, NOESY of compound 3a, 2D COSY of 3b (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
References
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n-Bu2O for 12 h only gave about 15% complex 3b and 10%
demetalated product 4b along with some side products, none of
which was starting material. Attempts to separate and unambigu-
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1
mixture was found to contain alkene protons as evidenced by H
NMR. The IR spectrum indicated the presence of a five-membered
lactam (1688 cm-1). Most likely analogues of 9 and 9′ are formed,
and the reaction needs more time to reach completion. The second
cyclization is slow, which might be due to the steric effect of the
methoxy group close to the reaction site. Optimization of the
reaction conditions (0.004 mol/L, 24 h) led to the formation of a
1:1 ratio (1H NMR) of 3b and 4b in 54% combined yield.
Demetalation of a spiromethoxycyclohexadiene-Fe(CO)3 during
cyclization was also seen in our earlier work.6 Nevertheless, the
reaction mixture was converted to 4b in almost quantitative yield.
The relatively lower yield is tentatively attributed to the demeta-
lation of the monocyclized product on prolonged heating.
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Iron carbonyl complexes prefer to be coupled with electron-
deficient olefins7 and only highly electron-deficient alkenes were
reported to undergo intermolecular coupling with diene-Fe(CO)3
JA0210188
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