An iron-promoted aldehyde-diene cyclocoupling reaction

Article abstract of DOI:10.1021/jo071124y

(Chemical Equation Presented) A stereospecific intramolecular iron tricarbonyl-promoted aldehyde-diene cyclocoupling reaction was investigated by using simple substrates 6 and more complicated substrates 30a/30b. Demetalation of the initial products conve

Full text of DOI:10.1021/jo071124y

An Iron-Promoted Aldehyde-Diene Cyclocoupling Reaction
Anthony J. Pearson* and Huikai Sun
Department of Chemistry, Case Western ReserVe UniVersity, CleVeland, Ohio 44106
ajp4@case.edu
ReceiVed June 13, 2007
A stereospecific intramolecular iron tricarbonyl-promoted aldehyde-diene cyclocoupling reaction was
investigated by using simple substrates 6 and more complicated substrates 30a/30b. Demetalation of the
initial products converts all complexed dienes to their pure organic counterparts. In addition, the nickel-
catalyzed carbonyl-ene reaction and the Prins reaction were investigated with two different substrates.
Introduction
Results and Discussion
To expand the scope of this iron tricarbonyl-promoted
cyclization reaction, we examined the reactivity of substrates
6a-c and 7, each having a pendant carbonyl group, in
anticipation that a carbonyl-ene-type of spirocyclization could
also be promoted by iron to afford products with a functional-
izable hydroxyl group at C4. Complexes 6a-c were readily
prepared in good yields starting with iron complexed dienyl-
carboxylic acids 4a-c5,6 through amidation followed by ester
to aldehyde reduction with DIBAl-H at low temperature
(Scheme 2). Treatment of 6a with MeMgBr at -78 °C followed
by in situ Mukaiyama oxidation of the alkoxide afforded
substrate 7 with a pendant ketone in 62% yield over two steps.7
With these substrates in hand, we investigated their reactivity
under various cyclization conditions previously found to effect
diene/alkene cyclocoupling. Substrate 6a was subjected to
thermal cyclization conditions (n-Bu2O, CO, 145 °C) and the
anticipated spirolactam complex 8a was isolated in only 4%
yield with loss of most starting material (Table 1, entry 1).
An intramolecular iron tricarbonyl promoted [6+2] ene type
of spirocyclization reaction has been developed in our labora-
tory.1 This reaction is based on substrates with a cyclohexadi-
eneiron tricarbonyl moiety and a pendant olefin and affords two
diastereomeric spirocyclic iron complexes, which can be readily
converted to organic molecules by subsequent demetalation
reactions (Scheme 1). The new carbon-carbon bonds (C4 and
C5 in compounds 2a/2b) are formed stereospecifically, but
thermal rearrangement leads to isomerization of 2a to 2b by
iron-mediated hydride shift. Further investigation showed this
regioisomerization problem can be remedied through tandem
double cyclization2 or introduction of certain functional groups
on the cyclohexadiene ring,1,3 and excellent dynamic diaste-
reoselectivity can also be obtained by introducing a chiral center
on the side chain.4 However, formation of a nonfunctionalized
alkyl group at C4 limits the application of this spirocyclization
reaction in organic synthesis.
(5) (a) Birch, A. J.; Pearson, A. J. J. Chem. Soc., Perkin Trans. 1 1978,
638-642. (b) Biffin, M. E. C.; Moritz, A. G.; Paul, D. B. Aust. J. Chem.
1972, 25, 1329-1334.
(6) (a) Kaliappan, K.; Rao, G. S. R. S. J. Chem. Soc., Perkin Trans. 1
1997, 3387-3392. (b) Birch, A. J.; Chamberlain, K. B.; Haas, M. A.;
Thompson, D. J. J. Chem. Soc., Perkin Trans. 1 1982, 1763-1769.
(7) Wada, A.; Hiraishi, S.; Takamura, N.; Date, T.; Aoe, K.; Ito, M. J.
Org. Chem. 1997, 62, 4343-4348.
(1) Pearson, A. J.; Zettler, M. W. J. Am. Chem. Soc. 1989, 111, 3908-
3918.
(2) Pearson, A. J.; Wang, X. J. Am. Chem. Soc. 2003, 125, 13326-
13327.
(3) Pearson, A. J.; Wang, X.; Dorange, I. B. Org. Lett. 2004, 6, 2535-
2538.
(4) Pearson, A. J.; Sun, H.; Wang, X. J. Org. Chem. 2007, 72, 25472557.
10.1021/jo071124y CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/07/2007
J. Org. Chem. 2007, 72, 7693-7700
7693

Pearson and Sun
TABLE 1. Cyclization of Substrates 6a-c
cyclization to give a single product 8c but in only 7% yield
(Table 1, entry 8). Substantial amounts of polar, uncharacter-
izable material were also formed during this reaction. Subjection
of ketone substrate 7 to photothermal cyclization conditions gave
uncyclized regioisomers from diene rearrangement and no
cyclization products were observed.
This intramolecular iron tricarbonyl-promoted carbonyl-ene
spirocyclization likely proceeds via a mechanism similar to the
all-carbon [6+2] ene type of spirocyclization reported earlier.1
Under either thermal or photothermal conditions, one carbonyl
ligand is dissociated from the iron atom in substrate 6a to lead
to a 16e iron complex 12 with a vacant coordination site, which
can be occupied by η2 coordination of the iron atom with the
aldehyde carbonyl double bond to form intermediate 13 (Scheme
3). Subsequent cyclization gives π allyl complex 14 followed
by hydride migration to afford 15. Then reductive elimination
followed by recapture of one carbonyl group affords product
8a, which can undergo diene migration through intermediates
16 and 17 under the reaction conditions to give regioisomer
10a as a minor product. Generally, iron-promoted [6+2] ene
spirocyclization affords these two regioisomers in equivalent
amounts, but this carbonyl-ene reaction gives the directly
formed lactam 8a as the major product. This stereoselectivity
is likely due to coordination of the iron atom with the newly
formed hydroxyl group in a 16e complexed intermediate 16,
formed through dissociation of one carbonyl from 8a under the
reaction conditions, which stabilizes 16. This coordination effect
geometrically favors the position for the diene in the 16e
intermediate 16 and disfavors postcyclization diene migration
to form intermediate 17, which can lead to minor product 10a.
To investigate the capability of this iron-promoted carbonyl-
ene reaction for formation of a 6-membered lactam, substrate
18 was prepared in good yield through homologation of
aldehyde 6a as shown in Scheme 4.9 Subjection of 18 to
photothermal conditions gave complexed secondary amide 19
as the sole product in 46% yield instead of formation of a
6-membered lactam. Thermal cyclization conditions gave similar
results with formation of some unidentified demetalated prod-
ucts. Considering the side chain structure of 18, a retro-Michael
reaction to generate 19 is not unexpected under these reaction
conditions.
18-Deoxycytochalasin H (Scheme 5) is a potent HIV-1
protease inhibitor and its derivatives can regulate plant growth.10
Through retrosynthetic analysis, this natural product might be
accessible from intermediate 20, which comprises a tricyclic
core structure with a 5-membered lactam, and this compound
might be prepared from complexed aldehydes 22a/b through
this iron-promoted aldehyde-diene reaction with formation of
a single complexed product 21. The desired substrates 22a/b
might be available from known complexes 23a/b, which have
been obtained through an Fe(CO)3-promoted [6+2] ene spiro-
cyclization in excellent diastereoselectivity during our previous
work.4
Before applying this iron-mediated aldehyde-diene coupling
reaction to the synthesis of intermediate 21 for a projected total
synthesis of 18-deoxycytochalasin H, a model reaction was
designed and studied based on simple substrates. Accordingly,
complexes 30a/b and 31a/b were prepared starting with
commercially available aminoalcohol 24, which was protected
products (%)b
time
(h)
entry
substrate
conditionsa
8
9
10
11
1
2
3
4
5
6
7
8
6a
6a
6a
6a
6a
6a
6b
6c
A
B
C
D
E
E
C
E
8
12
6
4
17
28
18
47
35
20
7
5
8
12
8
4
6
6
12
20
6
6
4
7
6
5
4
12
a Conditions: (A) n-Bu2O, 145 °C; (B) benzene, 350 nm, 80 °C; (C)
toluene, 350 nm, 110 °C; (D) mesitylene, 350 nm, 160 °C; (E) toluene,
350 nm, 100 °C. b Isolated percent yields.
SCHEME 1
Photothermal cyclization (benzene, 350 nm, CO, 80 °C) afforded
8a in better yield (17%) with 42% recovered starting material
(Table 1, entry 2). Under these conditions, several minor side
products were also observed, among which only one could be
purified and fully characterized as the decomplexed monoolefi-
nyl lactam 11a, obtained in 5% yield. The hydrogen source for
formation of this monoolefin compound has not been determined
at this time. When the cyclization of 6a was attempted under
various conditions by changing solvent, reaction temperature,
and reaction time (Table 1, entries 3-6), it was found that
prolonged reaction time and higher temperature usually caused
loss of material. Finally, the best results were obtained under
photothermal conditions in toluene at 100 °C, which afforded
both expected products 8a (47%), 10a (7%), demetalated
product 9a (6%) and side product 11a (8%). The combined yield
for both diene regioisomers was 60% in an 8:1 ratio ((8a +
9a)/10a). Complexed 8a was readily demetalated by CuCl2 in
EtOH to provide 9a in 79% yield.8
Cyclization of methyl-substituted complex 6b under photo-
thermal conditions afforded a 4:1 mixture of regioisomeric
spirolactam complexes 8b and 10b in 25% combined yield
(Table 1, entry 7). Methoxy-substituted substrate 6c underwent
(9) Demeke, D.; Forsyth, C. J. Org. Lett. 2003, 5, 991-994.
(10) Haidle, A. M.; Myers, A. G. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 12048-12053.
(8) Thompson, D. J. J. Organomet. Chem. 1976, 108, 381-383.
7694 J. Org. Chem., Vol. 72, No. 20, 2007

An Iron-Promoted Aldehyde-Diene Cyclocoupling Reaction
SCHEME 2
SCHEME 3
directly to give the desired products, but 30b needs to be
converted to 30a first via thermal equilibrium under the
cyclization conditions, and then undergoes cyclization.1 Com-
plex 32 was readily converted to pure organic compound 33
by demetalation with CuCl2 in EtOH, and the combined yield
for formation of 33 was 42% over two steps. The stereochem-
istry at C6 and C7 in compound 33 was assigned by NOE
difference NMR spectra. A 1.6:1 mixture of known1 compounds
34a/b was also isolated in 17% yield, resulting from iron-
promoted decarbonylation of 30a/b.
To compare this iron-promoted carbonyl-diene reaction with
the known nickel-catalyzed carbonyl-diene coupling reaction,13
decomplexed aldehydes 35a/b were prepared in good yields
from complexed alcohols 29a/b by demetalation and subsequent
oxidation with Dess-Martin reagent (Scheme 8). Treatment of
35a with Ni(acac)2 and Et2Zn in THF afforded two isomers in
9% and 52% yields, respectively. They were assigned as 36a
and 36b based on the known characteristics of this nickel-
catalyzed reaction and further confirmed by NMR spectra.
Subsequent oxidation of 36a and 36b with Dess-Martin reagent
gave two ketone isomers 37a and 37b, which further confirmed
that 36a and 36b are a pair of regioisomers instead of two
alcohol epimers. Similarly, 35b was also treated with Ni(acac)2
and Et2Zn in THF to afford 38a and 38b, each in 11% yield.
An increased amount of Ni(acac)2 and Et2Zn and an elongated
reaction time caused loss of most material. Subsequent oxidation
of 38a and 38b with Dess-Martin reagent also afforded two
ketone isomers 39a and 39b in excellent yields. For this type
of substrate, this comparison shows that our iron-promoted
carbonyl-ene reaction has the advantage of affording a single
major ene product with retention of the diene functional group.
Cyclization of 31a/b was also investigated under both thermal
and photothermal conditions and produced three regioisomers
40a-c with formation of a five-membered ring instead of the
expected six-membered ring. A plausible mechanism for this
reaction is included in Scheme 9. One carbonyl ligand dissoci-
ates from iron under the reaction conditions and then subsequent
oxidative addition of the aldehyde leads to intermediate 41, on
which decarbonylation occurs to give intermediate 42. Then
reductive elimination forms π allyl complex 43, which can
undergo a second reductive elimination and demetalation to
afford 40b or 40c. Presumably 40a results from double bond
and then oxidized (Swern oxidation) to give aldehyde 25 in 88%
yield over two steps (Scheme 6).11 Treatment of 25 with triethyl
phosphonoacetate under Masamune-Roush conditions,12 fol-
lowed by deprotection of the amino group afforded 26 in 73%
yield over two steps. Coupling of acid 4a via its acyl mesylate
with secondary amine 26 afforded amide complex 27 (76%
yield) with a pendant olefin, which underwent [6+2] ene type
spirocyclization under photothermal conditions to give a 1.7:1
mixture of lactam complexes 28a and 28b in 78% yield.
Attempted direct reduction of ester 28 to aldehyde 30 with
DIBAl-H was problematic. Aldehydes 30a/b (as a 3.5:1 mixture)
were therefore obtained by reducing esters 28a/b with LiBH4
to the corresponding alcohols 29a and 29b, obtained in a 1.4:1
ratio and 82% yield, followed by Mukaiyama oxidation.
Presumably, the changes in ratio of a/b are a result of
fractionation during these transformations, possibly reflecting
different stabilities or reactivities of these isomers. Homologation
of aldehydes 30a/b by treatment with MeOCHdPPh3 under
Wittig olefination conditions and subsequent hydrolysis afforded
aldehyde substrates 31a/b in a 4:1 ratio and 88% yield over
two steps.9
Subjection of 30a/b to photothermal conditions (mesitylene,
350 nm, CO, 160 °C) gave a single complexed tricyclic
compound 32 and its demetalation product 33 in 21% and 26%
yields, respectively (Scheme 7). Complex 30a can cyclize
(11) Dondoni, A.; Perrone, D.; Merino, P. J. Org. Chem. 1995, 60, 8074-
8080.
(13) (a) Shibata, K.; Kimura, M.; Shimizu, M.; Tamaru, Y. Org. Lett.
2001, 3, 2181-2183. (b) Sato, Y.; Takimoto, M.; Mori, M. Tetrahedron
Lett. 1996, 37, 887-890. See also: (c) Jang, H-Y.; Huddleston, R. R.;
Krische, M. J. Angew. Chew., Int. Ed. 2003, 42, 4074-4077.
(12) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183-
2186.
J. Org. Chem, Vol. 72, No. 20, 2007 7695

Pearson and Sun
SCHEME 4
SCHEME 5
and then with CO for 10 min. The solution was refluxed under a
balloon of CO for 6-20 h. The cooled reaction mixture was filtered
through Celite and concentrated in vacuo. Flash chromatography
or preparative TLC separation yielded the desired products.
Deviations from this procedure are noted in the experimental
description for specific compounds.
migration on the initial products. Note that substrate 30 also
gives products of decarbonylation (34) but there is no decar-
bonylative cyclization because this would require 4-membered-
ring formation.
To investigate alternate cyclization methods that can avoid
decarbonylation, a 1:2.7 mixture of 44a/b was prepared in 57%
yield by treating complexes 31a/b with Me3NO in benzene
(Scheme 10). Subsequent treatment of the 44a/b mixture with
2 N HCl led to 100% recovery of 44b and cyclization product
45 in 75% yield from its corresponding substrate 44a, which
was completely consumed after the reaction (path a in Scheme
10). A better combined yield for formation of 45, 63% over
two steps from 31a/b, was obtained by demetalation with CuCl2
in EtOH, followed by direct treatment of the product mixture
with 2 N HCl (path b in Scheme 10). These results indicate 45
is formed through a Prins reaction from demetalated compound
44a rather than a hetero-Diels-Alder reaction.14 However, due
to difficulty in forming a seven-membered ring with the diene
in 44b, this compound does not undergo the Prins reaction and
remains unchanged under the conditions used here.
To conclude, an intramolecular iron-promoted aldehyde-
diene coupling reaction was discovered and investigated to
provide spirocyclic or bicyclic products. The ability to ste-
reospecifically build new chiral centers, introduce a function-
alizable hydroxyl group, and avoid isomerization of products
significantly expands the scope of our previously reported [6+2]
ene type of spirocyclization and tandem double cyclization.
General Procedure for the Photothermally Induced Cycliza-
tion. The appropriate amide was dissolved in freshly distilled
toluene or mesitylene (0.01-0.02 mmol/mL) under argon in a dried
quartz tube or a glass round-bottomed flask. The air in the solution
was removed by the freeze-pump-thaw method three times,
followed by bubbling with Ar for 10 min and then with CO for 10
min. The reaction flask was put into an oil bath, heated to the boiling
point of the solvent being used, and irradiated in a Rayonet reactor
with a 350 nm light source, with magnetic stirring for 6-24 h under
a balloon of CO. The cooled reaction mixture was filtered through
Celite and concentrated in vacuo. Mesitylene was removed under
oil pump vacuum at rt. Flash chromatography or preparative TLC
separation yielded the desired products. Deviations from this
procedure are noted in the experimental description for specific
compounds.
General Procedure for Demetalation. Method A: To the
solution of complexed intermediate in benzene was added trim-
ethylamine oxide (30 equiv). The reaction mixture was stirred for
24 h at rt, then filtered through Celite and concentrated in vacuo.
Purification by flash chromatography or preparative TLC afforded
the pure products. Method B: To a small vial was added the iron
carbonyl complex (0.1 mmol) and sat. CuCl2 solution in EtOH (2.5
mL). The solution was stirred at rt for 3-24 h, then concentrated
in vacuo. After water (4 mL) was added to the residue, the mixture
was extracted with ether (3 × 3 mL). The organic layer was washed
with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The
crude products were purified by preparative TLC or flash chroma-
tography.
Experimental Section
General Procedure for the Thermally Induced Cyclization.
The appropriate amide was dissolved in freshly distilled n-Bu2O
ether (0.02 mmol/mL) under argon in a dried glass round-bottomed
flask. The air in the solution was removed by the freeze-pump-
thaw method three times, followed by bubbling with Ar for 10 min
Cyclization of 6a To Afford 8a, 9a, 10a, and 11a. According
to the general procedure for the photothermally induced cyclization,
a solution of aldehyde 6a (43 mg, 0.11 mmol) in toluene (22 mL)
was heated at 100 °C for 12 h. Flash chromatography (Hex:EA/
3:1) afforded 8a (20.2 mg, 47%) as a pale yellow solid. Mp 189-
191 °C. Rf 0.60 (Hex:EA/2:1). 1H NMR (400 MHz, CDCl3) δ 7.57
(dd, J ) 9.2, 1.6 Hz, 2H), 7.37-7.33 (2H), 7.13 (t, J ) 7.2 Hz,
(14) (a) Prins, H. J. Chem. Weekbl. 1919, 16, 1072-1073. (b) Yadav, J.
S.; Reddy, B. V. S.; Kumar, G. M.; Murthy, C. V. S. R. Tetrahedron Lett.
2001, 42, 89-91.
7696 J. Org. Chem., Vol. 72, No. 20, 2007

An Iron-Promoted Aldehyde-Diene Cyclocoupling Reaction
SCHEME 6
SCHEME 7
1H), 5.72-5.69 (m, 1H), 5.51 (dd, J ) 5.6, 5.2 Hz, 1H), 4.40-
4.30 (m, 1H), 3.94 (dd, J ) 10.4, 4.8 Hz, 1H), 3.68 (dd, J ) 10.8,
2.4 Hz, 1H), 3.21-3.18 (m, 1H), 3.09 (dd, J ) 6.8, 1.2 Hz, 1H),
2.19 (br, 1H), 1.92-1.81 (2H). 13C NMR (100 MHz, CDCl3) δ
211.7, 175.1, 139.5, 129.1, 124.8, 119.7, 86.8, 85.2, 74.4, 60.3,
57.8, 54.8, 53.1, 37.2. HRMS (FAB) calcd for MH+ (C18H16FeNO5)
382.0378, found 382.0378. Purification of the remaining material
by preparative TLC (2% MeOH in CH2Cl2) gave recovered starting
material (7.0 mg, 8%) and afforded 10a (2.9 mg, 7%) as a pale
found 242.1173. 9a (1.6 mg, 6%). Mp 155-157 °C. Rf 0.40 (2%
1
MeOH in CH2Cl2) H NMR (400 MHz, CDCl3) δ 7.66 (dd, J )
9.2, 1.2 Hz, 2H), 7.41-7.30 (2H), 7.18-7.15 (m, 1H), 6.36 (dd, J
) 9.6, 5.2 Hz, 1H), 6.06-6.02 (m, 1H), 5.92-5.87 (m, 1H), 5.74
(d, J ) 9.6 Hz, 1H), 4.40-4.37 (m, 1H), 4.04 (dd, J ) 10.8, 5.6
Hz, 1H), 3.73 (dd, J ) 10.4, 3.2 Hz, 1H), 2.88 (d, J ) 18.0 Hz,
1H), 2.21 (dd, J ) 18.0, 5.6 Hz, 1H), 1.96 (d, J ) 3.6 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 175.9, 139.4, 129.2, 125.4, 125.0,
124.0, 121.8, 120.1, 70.0, 53.0, 51.4, 30.0. HRMS (FAB) calcd
for MH+ (C15H16NO2) 242.1181, found 242.1145. 11a (2.2 mg,
1
yellow solid. Mp 50 °C dec. Rf 0.50 (2% MeOH in CH2Cl2). H
NMR (400 MHz, CH3OD:CDCl3/1:1) δ 7.62-7.58 (2H), 7.39-
7.34 (2H), 7.19-7.15 (m, 1H), 5.57 (dd, J ) 5.6, 4.2 Hz, 1H),
5.39-5.36 (m, 1H), 4.29 (dd, J ) 10.8, 4.4 Hz, 1H), 3.69 (d, J )
11.2 Hz, 1H), 3.48-3.40 (m, 1H), 2.84 (dd, J ) 6.4, 1.2 Hz, 1H),
2.35 (dd, J ) 16.0, 3.2 Hz, 1H), 1.93 (dd, J ) 16.0, 1.6 Hz, 1H).
13C NMR (100 MHz, CH3OD:CDCl3/1:1) δ 211.5, 176.4, 139.6,
129.1, 124.9, 120.0, 88.8, 82.2, 71.8, 63.8, 60.8, 55.1, 54.7, 31.1.
HRMS (FAB) calcd for [MH+ - Fe(CO)3] (C15H16NO2) 242.1181,
1
8%). Mp 195-197 °C. Rf 0.30 (2% MeOH in CH2Cl2). H NMR
(400 MHz, CDCl3) δ 7.65 (dd, J ) 9.2, 1.2 Hz, 2H), 7.40-7.35
(2H), 7.17-7.13 (m, 1H), 6.28 (ddd, J ) 10.0, 4.0, 3.6 Hz, 1H),
5.68 (d, J ) 10.0 Hz, 1H), 4.26-4.22 (m, 1H), 4.09 (dd, J ) 10.4,
5.6 Hz, 1H), 3.71 (dd, J ) 10.4, 3.2 Hz, 1H), 2.23-2.05 (2H),
2.00-1.90 (2H), 1.89 (d, J ) 4.8 Hz, 1H), 1.75-1.62 (2H). 13C
NMR (100 MHz, CDCl3) δ 175.7, 139.6, 135.8, 129.1, 124.8, 122.2,
J. Org. Chem, Vol. 72, No. 20, 2007 7697

Pearson and Sun
SCHEME 8
a Yields are based on the corresponding single alcohol.
SCHEME 9
7.33 (2H), 7.16-7.12 (m, 1H), 5.47 (d, J ) 4.0 Hz, 1H), 5.20 (dd,
J ) 6.0, 4.0 Hz, 1H), 4.31-4.28 (m, 1H), 4.22 (dd, J ) 11.2, 4.4
Hz, 1H), 3.71 (d, J ) 10.8 Hz, 1H), 2.62 (dd, J ) 6.4, 1.2 Hz,
1H), 2.34 (d, J ) 16.0 Hz, 1H), 1.96-1.91 (2H), 1.72 (s, 3H). 13
C
NMR (100 MHz, CDCl3) δ 175.5, 139.7, 129.1, 124.8, 119.6, 91.0,
80.3, 78.5, 72.6, 59.7, 55.5, 54.6, 36.9, 25.8. HRMS (FAB) calcd
for MH+ (C19H18FeNO5) 396.0534, found 396.0542.
Cyclization of 6c To Afford 8c. According to the general
procedure for the photothermally induced cyclization, aldehyde 6c
(29 mg, 0.07 mmol) in toluene (15 mL) was heated at 100 °C for
12 h. Preparative TLC (Hex:EA/2:1) afforded 8c (1.9 mg, 7%). Rf
0.70 (Hex:EA/2:1). 1H NMR (400 MHz, CDCl3) δ 7.62-7.59 (2H),
7.36-7.32 (2H), 7.15-7.11 (m, 1H), 5.26-5.24 (m, 1H), 4.22-
4.19 (m, 1H), 3.94 (dd, J ) 10.8, 4.4 Hz, 1H), 3.77 (s, 3H), 3.70
(dd, J ) 10.8, 1.6 Hz, 1H), 3.39 (d, J ) 2.4 Hz, 1H), 2.74-2.70
(m, 1H), 2.25 (br, 1H), 1.75 (ddd, J ) 14.8, 2.4, 0.8 Hz, 1H), 1.63
(dd, J ) 14.8, 3.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 175.4,
141.3, 139.2, 128.8, 124.6, 119.4, 73.7, 67.6, 56.5, 55.2, 53.2, 51.6,
48.2, 36.7. HRMS (FAB) calcd for MH+ (C19H18FeNO6) 412.0484,
found 412.0487.
120.0, 73.3, 53.4, 52.0, 29.4, 24.9, 19.0. HRMS (FAB) calcd for
MH+ (C15H18NO2) 244.1337, found 244.1331.
[N-Phenylcyclohexa-1,3-dienecarboxamide]tricarbonyliron (19).
According to the general procedure for the photothermally induced
cyclization, a solution of aldehyde 18 (31 mg, 0.09 mmol) in
mesitylene (16 mL) was heated at 160 °C for 12 h. Flash
chromatography (Hex:EA/3:1) recovered starting material (5.5 mg,
Demetalation of 8a To Afford 9a. According to the general
procedure B of demetalation, complex 8a (11 mg, 29 µmol) was
treated with CuCl2 in EtOH for 20 h. The crude products were
purified by preparative TLC to give 9a (5.5 mg, 79%).
Cyclization of 6b To Afford 8b and 10b. According to the
general procedure for the photothermally induced cyclization, a
solution of aldehyde 6b (23 mg, 0.06 mmol) in toluene (5.8 mL)
was heated at 110 °C for 6 h. Flash chromatography (Hex:EA/3:1)
afforded 8b (4.5 mg, 20%) as a pale yellow solid. Mp 158
1
18%) and afforded 19 (12 mg, 46%). Rf 0.50 (Hex:EA/2:1). H
NMR (400 MHz, CDCl3) δ 7.47-7.45 (2H), 7.29-7.24 (3H),
7.06-7.02 (m, 1H), 6.16 (dd, J ) 4.0, 0.8 Hz, 1H), 5.39-5.37 (m,
1H), 3.30-3.28 (m, 1H), 1.98-1.93 (2H), 1.75-1.64 (2H). 13C
NMR (400 MHz, CDCl3) δ 169.6, 138.1, 129.3, 124.5, 120.4, 88.6,
85.0, 68.0, 61.8, 25.1, 24.7. HRMS (FAB) calcd for MH+ (C16H14-
FeNO4) 340.0272, found 340.0272.
[Ethyl 2-[6,9,η-2-phenyl-1-oxo-2-azaspiro[4.5]deca-6,8-dien-
4-yl]acetate]tricarbonyliron (28a and 28b). According to the
general procedure for the photothermally induced cyclization,
complex 27 (104 mg, 0.23 mmol) in benzene (15 mL) was heated
at 80 °C under CO in a quartz tube (Rayonet reactor) for 6 h. Flash
chromatography (Hex:EA/4:1) afforded two inseparable diastere-
omers 28a and 28b (81 mg, 78%) in a 1.7:1 ratio. Rf 0.50 (Hex:
EA/4:1). 1H NMR (400 MHz, CDCl3) δ 7.62-7.56 (4H, two
isomers), 7.37-7.32 (4H, two isomers), 7.15-7.10 (2H, two
1
-160 °C. Rf 0.70 (Hex:EA/2:1). H NMR (400 MHz, CDCl3) δ
7.59-7.56 (2H), 7.36-7.32 (2H), 7.15-7.11 (m, 1H), 5.41 (d, J
) 6.4 Hz, 1H), 4.20-4.16 (m, 1H), 3.93 (dd, J ) 11.2, 4.8 Hz,
1H), 3.70 (dd, J ) 10.8, 2.0 Hz, 1H), 3.04 (d, J ) 1.6 Hz, 1H),
3.02-2.99 (m, 1H), 2.31 (s, 3H), 2.16 (d, J ) 4.0 Hz, 1H), 1.83-
1.72 (2H). 13C NMR (100 MHz, CDCl3) δ 211.9, 175.6, 139.5,
129.1, 124.8, 119.8, 104.2, 86.4, 74.3, 60.6, 56.4, 55.9, 53.4, 36.7,
22.6. HRMS (FAB) calcd for MH+ (C19H18FeNO5) 396.0534, found
396.0552. Further purification of the remaining material by prepara-
tive TLC (2% THF in CH2Cl2) gave recovered 6b (4.5 mg, 19%)
and afforded 10b (1.2 mg, 5%). Mp 170 °C dec. Rf 0.20 (2% THF
in CH2Cl2). 1H NMR (400 MHz, CDCl3) δ 7.64-7.60 (2H), 7.38-
7698 J. Org. Chem., Vol. 72, No. 20, 2007

An Iron-Promoted Aldehyde-Diene Cyclocoupling Reaction
SCHEME 10
isomers), 5.55-5.53 (m, 1H, minor isomer), 5.51-5.49 (2H, major
isomers), 5.34-5.31 (m, 1H, minor isomer), 4.18 (q, J ) 7.6 Hz,
2H, major isomer), 4.14-4.05 (2H, minor isomer), 3.90 (dd, J )
14.4, 6.8 Hz, 1H, major isomer), 3.58-3.53 (2H, two isomers),
3.41-3.39 (m, 1H, minor isomer), 3.32-3.25 (m, 1H, major
isomer), 3.02 (dd, J ) 6.4, 1.2 Hz, 1H, minor isomer), 2.88 (dd, J
) 15.2, 3.2 Hz, 1H, major isomer), 2.78-1.88 (10H, two isomers),
1.29 (t, J ) 7.2 Hz, 3H, major isomer), 1.22 (t, J ) 6.8 Hz, 3H,
minor isomer). 13C NMR (100 MHz, CDCl3) δ 211.7, 211.5, 176.2,
175.9, 172.2, 172.1, 139.8, 139.6, 129.1, 129.0, 124.8, 120.0, 119.6,
119.5, 89.0, 87.8, 83.6, 82.2, 63.2, 63.1, 62.2, 61.1, 59.0, 51.5, 50.0,
40.8, 39.7, 34.0, 33.5, 14.4, 14.3. HRMS (FAB) calcd for MH+
(C22H22FeNO6) 452.0797, found 452.0790.
[2-[6,9,η-2-Phenyl-1-oxo-2-azaspiro[4.5]deca-6,8-dien-4-yl]e-
thanol]tricarbonyliron (29a and 29b). To a solution of esters 28a
and 28b (451.0 mg, 1.0 mmol) in Et2O (28 mL) under Ar was
added LiBH4 (110.0 mg, 5.0 mmol) in one portion. Stirring was
continued for 12 h and the reaction was complete according to TLC.
The reaction mixture was quenched with 1 N HCl (25 mL) at
0 °C, extracted with Et2O (3 × 25 mL), washed with brine (2 ×
15 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Flash
chromatography (Hex:EA/4:1) afforded two inseparable diastere-
omers 29a and 29b (337.0 mg, 82%) in a 1.4:1 ratio. Rf 0.30 (Hex:
EA/2:1). 1H NMR (400 MHz, CDCl3) δ 7.55-7.50 (4H, two
isomers), 7.30-7.25 (4H, two isomers), 7.10-7.05 (2H, two
isomers), 5.55-5.45 (m, 1H, minor isomer), 5.43-5.38 (2H, major
isomer), 5.26-5.23 (m, 1H, minor isomer), 4.04 (dd, J ) 14.4, 6.4
Hz, 1H, minor isomer), 3.77-3.51 (7H, two isomers), 3.35-3.32
(m, 1H, minor isomer), 3.26-3.23 (m, 1H, major isomer), 2.96
(dd, J ) 6.4, 1.6 Hz, 1H, minor isomer), 2.74 (dd, J ) 6.4, 1.6 Hz,
1H, major isomer), 2.38-2.32 (m, 1H, minor isomer), 2.18-2.14
(m, 1H, major isomer), 2.12-2.06 (m, 1H, major isomer), 2.03
(dd, J ) 16.0, 2.8 Hz, 1H, major isomer), 1.97 (d, J ) 3.2 Hz, 2H,
minor isomer), 1.81 (dd, J ) 15.6, 3.2 Hz, 1H, major isomer), 1.77-
1.70 (m, 1H, minor isomer), 1.66-1.31 (5H, two isomers). 13C
NMR (100 MHz, CDCl3) δ 211.9, 211.7, 177.0, 176.6, 139.9, 139.8,
129.1, 129.0, 124.7, 124.6, 119.7, 119.6, 89.0, 87.9, 83.2, 82.3,
63.6, 63.5, 62.6, 61.2, 60.9, 59.7, 52.2, 51.6, 50.3, 49.9, 41.7, 39.8,
39.5, 33.2, 31.5, 30.7. HRMS (FAB) calcd for MH+ (C20H20FeNO5)
410.0691, found 410.0692.
mixture was allowed to warm to rt and stirred for 2.5 h. The reaction
solution was quenched with brine (10 mL), extracted with Et2O (2
× 10 mL), washed with a mixture of brine and water (1:1, 2 × 5
mL), dried (Na2SO4), filtered and concentrated in vacuo. Flash
chromatography (Hex:EA/3:1) afforded 30a and 30b (118 mg, 76%
combined yield) in a 3.5:1 ratio. 30a (91.7 mg, 59%): Rf 0.50 (Hex:
1
EA/2:1). H NMR (400 MHz, CDCl3) δ 9.85 (s, 1H), 7.51-7.48
(2H), 7.29-7.25 (2H), 7.08-7.04 (m, 1H), 5.46-5.44 (2H), 3.91
(dd, J ) 10.0, 6.4 Hz, 1H), 3.38 (dd, J ) 10.0, 4.2 Hz, 1H), 3.27-
3.24 (m, 1H), 3.02 (d, J ) 14.4 Hz, 1H), 2.65-2.53 (3H), 2.05
(dd, J ) 15.2, 2.8 Hz, 1H), 1.81 (dd, J ) 15.6, 2.8 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ 211.7, 200.4, 176.1, 139.5, 129.1, 124.9,
119.6, 87.9, 83.6, 62.4, 59.1, 51.3, 50.1, 43.0, 39.8, 38.4. HRMS
(FAB) calcd for MH+ (C20H28FeNO5) 408.0534, found 408.0531.
1
30b (26.2 mg, 17%): Rf 0.40 (Hex:EA/2:1). H NMR (400 MHz,
CDCl3) δ 9.72 (s, 1H), 7.53-7.51 (2H), 7.30-7.26 (2H), 7.09-
7.05 (m, 1H), 5.50-5.47 (m, 1H), 5.29-5.23 (m, 1H), 4.15 (ddd,
J ) 10.8, 6.0, 1.2 Hz, 1H), 3.34-3.32 (2H), 2.98 (dd, J ) 6.4, 1.2
Hz, 1H), 2.79-2.74 (m, 1H), 2.65-2.60 (m, 1H), 2.37 (ddd, J )
18.4, 11.2, 1.2 Hz, 1H), 2.02 (dd, J ) 15.6, 2.4 Hz, 1H), 1.83 (dd,
J ) 15.6, 3.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 211.5, 200.3,
175.9, 139.7, 129.1, 124.9, 119.5, 89.1, 82.3, 62.9, 62.9, 51.5, 50.9,
43.8, 36.6, 33.6. HRMS (FAB) calcd for MH+ (C20H28FeNO5)
408.0534, found 408.0527.
[2-[6,9,η-2-Phenyl-1-oxo-2-azaspiro[4.5]deca-6,8-dien-4-yl]-
propionaldehyde]tricarbonyliron (31a and 31b). To a mixture
of methoxytrimethylphosponium chloride (146 mg, 0.43 mmol) in
THF (3.3 mL) under Ar at 0 °C was added KHMDS (0.5 M in
toluene, 0.94 mL, 0.47 mmol). Stirring was continued at this
temperature for 30 min, then a solution of aldehyde 30a/b (133
mg, 0.33 mmol) in THF (2.0 mL) was added at -78 °C and the
reaction was maintained at this temperature for 1 h. The mixture
was allowed to warm to rt and stirring was continued for 1 h. The
reaction mixture was carefully quenched with brine (10 mL),
extracted with Et2O (3 × 7 mL), washed with brine (2 × 8 mL),
dried (Na2SO4), filtered, and concentrated in vacuo. The residue
was dissolved in dioxane (3.0 mL) and treated with 2 N HCl (1.0
mL) for 3 h. Et2O (50 mL) was added, then the solution was washed
with water (10 mL) and brine (10 mL), dried (Na2SO4), filtered,
and concentrated in vacuo. Flash chromatography (Hex:EA/3:1)
afforded inseparable 31a and 31b (120 mg, 88%) in a 4:1 ratio. Rf
0.60 (Hex:EA/2:1). 1H NMR (400 MHz, CDCl3) δ 9.84 (t, J ) 1.6
Hz, 1H, major isomer), 9.74 (t, J ) 1.6 Hz, 1H, minor isomer),
7.62-7.54 (4H, two isomers), 7.38-7.32 (4H, two isomers), 7.16-
7.11 (2H, two isomers), 5.55-5.52 (m, 1H, minor isomer), 5.51-
5.48 (2H, major isomer), 5.32-5.30 (m, 1H, minor isomer), 4.16-
4.10 (m, 1H, minor isomer), 3.75 (dd, J ) 10.0, 6.8 Hz, 1H, major
[2-[6,9,η-2-Phenyl-1-oxo-2-azaspiro[4.5]deca-6,8-dien-4-yl]ac-
etaldehyde]tricarbonyliron (30a and 30b). To a solution of
alcohol 29a/b (155 mg, 0.37 mmol) in THF (2.0 mL) under Ar at
0 °C was added isopropylmagnesium bromide solution (2 M in
THF, 0.24 mL, 0.47 mmol). After 30 min at 0 °C, a solution of
1,1′-(azodicarbonyl)dipiperidine (105.0 mg, 0.42 mmol) in THF
(1.0 mL) was added. Stirring was continued for 30 min, then the
J. Org. Chem, Vol. 72, No. 20, 2007 7699

Pearson and Sun
isomer), 3.48 (dd, J ) 10.0, 6.0 Hz, 1H, major isomer), 3.44-3.40
(2H, minor isomer), 3.32-3.28 (m, 1H, major isomer), 2.98 (dd, J
) 6.0, 0.8 Hz, 1H, minor isomer), 2.82-2.79 (m, 1H, major
isomer), 2.60-2.2.0 (6H, two isomers), 2.11-2.03 (4H, two
isomers), 1.91-1.71 (4H, two isomers). 13C NMR (100 MHz,
CDCl3) δ 211.8, 211.6, 201.2, 201.1, 176.6, 176.0, 139.6, 129.2,
129.1, 124.8, 119.6, 119.5, 89.0, 87.8, 83.6, 82.3, 63.4, 63.3, 62.2,
59.2, 52.2, 51.9, 50.1, 49.6, 43.9, 41.8, 41.4, 41.3, 39.9, 33.0, 21.4,
20.5. HRMS (FAB) calcd for MH+ (C21H20FeNO5) 422.0691, found
422.0711.
Cyclization of 30a/b To Afford Compounds 32 and 33.
According to the general procedure for the photothermally induced
cyclization, aldehydes 30a/b (15.1 mg, 37 µmol) in mesitylene (3.0
mL) was heated under CO at 160 °C for 9 h. Preparative TLC
(Hex:EA/3:1) recovered starting material (2.6 mg, 17%) and
afforded decarbonylated products 34a/b (2.4 mg, 17%), cyclization
product 32 (3.2 mg, 21% from 1H NMR, with some impurity), and
demetalated product 33 (2.6 mg, 26%). According to the general
demetalation procedure B, 33 was decomplexed by CuCl2 in EtOH
to afford 32 in 74% yield (42% combined yield over two steps).
33: Mp 138-140 °C. Rf 0.40 (Hex:EA/2:1). 1H NMR (400 MHz,
CDCl3) δ 7.62 (d, J ) 8.0 Hz, 2H), 7.33-7.29 (2H), 7.11-7.07
(m, 1H), 6.17-6.13 (m, 1H), 5.94 (dd, J ) 9.6, 4.2 Hz, 1H), 5.74
(dd, J ) 9.6, 4.4 Hz, 1H), 5.56 (d, J ) 9.6 Hz, 1H), 4.40-4.37
(m, 1H), 4.11 (dd, J ) 10.0, 7.6 Hz, 1H), 3.56 (d, J ) 14.4 Hz,
1H), 3.20-3.16 (m, 1H), 2.87 (dd, J ) 18.0, 7.6 Hz, 1H), 2.06-
2.01 (m, 1H), 1.81 (br, 1H), 1.38-1.31 (m, 1H). 13C NMR (100
MHz, CDCl3) δ 176.2, 139.7, 129.1, 125.6, 125.4, 125.0, 122.8,
122.3, 120.1, 77.5, 56.1, 50.6, 48.7, 44.1, 37.6. HRMS (FAB) calcd
for MH+ (C17H18NO2) 268.1338, found 268.1332.
9 h. Preparative TLC (Hex:EA/8:1) gave recovered starting material
(2.6 mg, 10%) and afforded decarbonylated cyclization products
40a (1.4 mg, 12%) and inseparable 40b and 40c (3.8 mg, 32%
combined yield) in a 1:5 ratio. 40a: Rf 0.35 (Hex:EA/8:1). 1H NMR
(400 MHz, CDCl3) δ 7.70-7.67 (2H), 7.39-7.34 (2H), 7.15-7.13
(m, 1H), 6.02-5.97 (m, 1H), 5.63-5.60 (m, 1H), 4.10 (dd, J )
10.0, 8.4 Hz, 1H), 3.52 (dd, J ) 10.0, 3.2 Hz, 1H), 2.60-2.54 (m,
1H), 2.51-2.45 (m, 1H), 2.25-2.12 (2H), 2.09-2.02 (m, 1H),
1.87-1.79 (2H), 1.61-1.56 (2H), 1.48-1.39 (m, 1H). 13C NMR
(150 MHz, CDCl3) δ 177.4, 140.0, 130.1, 129.0, 127.2, 124.6,
120.0, 59.2, 53.5, 42.1, 42.0, 32.4, 31.2, 25.1, 23.0. HRMS (FAB)
calcd for MH+ (C17H20NO) 254.1545, found 254.1546. 40b and
40c: Rf 0.40 (Hex:EA/8:1). 1H NMR (400 MHz, CDCl3) δ 7.71-
7.68 (4H, two isomers), 7.39-7.35 (4H, two isomers), 7.16-7.12
(2H, two isomers), 5.85-5.78 (2H, two isomers), 5.55-5.59 (2H,
two isomers), 4.09 (dd, J ) 10.0, 8.4 Hz, 1H, major isomer), 4.01
(dd, J ) 10.0, 8.4 Hz, 1H, minor isomer), 3.58 (dd, J ) 10.0, 2.0
Hz, 1H, minor isomer), 3.46 (dd, J ) 10.0, 2.0 Hz, 1H, major
isomer), 2.98-2.97 (m, 1H, major isomer), 2.60-1.40 (19H, two
isomers). 13C NMR (150 MHz, CDCl3) δ 179.2, 178.6 140.0, 139.8,
130.7, 129.0, 127.0, 126.9, 124.6, 124.5, 120.1, 119.9, 57.3, 57.0,
54.1, 53.2, 43.1, 40.5, 39.5, 37.3, 33.8, 32.7, 31.6, 30.8, 29.9, 28.8,
27.5, 26.7, 21.2. HRMS (FAB) calcd for MH+ (C17H20NO)
254.1545, found 254.1543.
Acknowledgment. We thank the National Science Founda-
tion for financial support (grant CHE-0449642).
Supporting Information Available: Experimental procedures
and spectroscopic data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Cyclization of 31a/b To Afford Compounds 40a, 40b, and
40c. According to the general procedure for the photothermally
induced cyclization, the mixture of aldehydes 31a/b (20.1 mg, 48
µmol) in mesitylene (4.8 mL) was heated under CO at 160 °C for
JO071124Y
7700 J. Org. Chem., Vol. 72, No. 20, 2007