Stereocontrolled intramolecular iron-mediated diene/vinyl ether cyclocoupling reactions

Article abstract of DOI:10.1021/jo301721d

A stereocontrolled intramolecular iron-mediated diene/olefin cyclocoupling reaction has been explored using vinyl ethers as the olefin partners. Spirolactams with functionalized (alkoxymethyl) side chains can be formed under thermal conditions. With a methoxy substituent on the diene, demetalation and hydrolysis of the cyclocoupling product afforded a single diastereomer.

Full text of DOI:10.1021/jo301721d

Note
pubs.acs.org/joc
Stereocontrolled Intramolecular Iron-mediated Diene/Vinyl Ether
Cyclocoupling Reactions
Anthony J. Pearson,* Sheng Zhang, and Huikai Sun
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, United States
S
* Supporting Information
ABSTRACT: A stereocontrolled intramolecular iron-mediated
diene/olefin cyclocoupling reaction has been explored using
vinyl ethers as the olefin partners. Spirolactams with function-
alized (alkoxymethyl) side chains can be formed under thermal
conditions. With a methoxy substituent on the diene,
demetalation and hydrolysis of the cyclocoupling product
afforded a single diastereomer.
ransition metal-promoted cyclocoupling reactions of
alkenes and alkynes have a rich history and occupy an
substituted cyclohexadieneiron complexes that we have
T
previously shown to afford a single diastereomer cyclohexenone
after demetalation and hydrolysis.5
important place in organic synthesis methodology. These
processes often complement their more traditional organic
counterparts in terms of stereochemistry and one’s ability to
carry out reactions that are symmetry forbidden or compro-
mised by more facile competing processes. While such
transformations in the coordination sphere of a metal are
usually not concerted single-step processes, they are never-
theless usually stereospecific, a result of continual attachment of
the reacting ligand(s) to the metal as the key bond-forming
steps proceed.1 Our group has developed a stereocontrolled
intramolecular iron-mediated diene/olefin cyclocoupling reac-
tion, equivalent to a [6 + 2] ene reaction, which forms
spirolactones, spirothiolactones and spirolactams under thermal
or photothermal conditions (eq 1, Y = CH2, Z = CH3).2 We
Previously reported3 aldehydes 3a and 3b were each reacted
with (methoxymethyl)triphenyl-phosphorane to afford me-
thoxy vinyl ethers 4a (E/Z = 2:1) and 4b (E/Z = 2:1)
(Scheme 1). We also planned to study the cyclizations of silyl
ether analogs of complexes 4, because a silyl protecting group is
easier to remove from the anticipated cyclization products
when required. Since the requisite silyl vinyl ethers can be
accessed from the aldehydes that are produced by hydrolysis of
the methyl vinyl ethers, we chose to use this method rather
than a more direct approach for the present study. Treatment
of 4a and 4b with 2 N HCl in dioxane afforded aldehydes 5a
and 5b, which were reacted with t-butyldimethylsilyl trifluor-
omethanesulfonate in the presence of Hunig’s base to give 6a
̈
(E/Z = 7:1) and 6b (E/Z = 5.5:1) in 84 and 80% yield,
respectively.
With substrates 4a/b and 6a/b in hand, we investigated their
reactivity in the diene/alkene cyclocoupling reaction. Refluxing
4a in n-Bu2O (0.02 mmol/mL) under CO atmosphere at 142
°C for 8 h generated an inseparable mixture of 7a/b (eq 2;
isomers a result from thermal rearrangement of the initial
products, isomers b2). The mixture was demetalated with
ethanolic CuCl26 to afford an inseparable mixture of 11a/b (eq
3). Subjection of 4b to the same thermal cyclization conditions
for 20 h similarly gave an inseparable mixture of 8a/b in 76%
combined yield (eq 2). Demetalation and in situ hydrolysis of
the mixture of 8a/b afforded a single product, α,β-unsaturated
ketone 12 (eq 4). Complex 6a was also subjected to thermal
cyclization conditions and gave two separable regioisomers, 9a
recently extended this reaction to include aldehydes (1, Y = O)
as the 2π component,3 which affords hydroxyl substituted
spirolactams (2, Z = OH) that embody in the organic moiety
key structural features of natural products such as the
spirostaphylotrichins.4 The work described in this report aims
to further expand the scope of the cyclocoupling reaction to
include vinyl ethers as the 2π component, which would result in
spirocyclic molecules having (protected) hydroxymethyl side
chains. We examined both methoxy- and t-butyldimethylsilyl
vinylethers on the side chain to access differently protected
hydroxymethyl groups; we also examined the use of methoxy-
Received: August 16, 2012
Published: September 5, 2012
© 2012 American Chemical Society
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Note
Scheme 1
Scheme 2
and 9b (eq 2). Demetalation of the mixture 9a/b with CuCl2
gave a complex mixture of products (according to TLC
inspection), possibly due to partial hydrolysis of the TBS ether,
which were not isolated and characterized. Demetalation of the
individual complexes using trimethylamine N-oxide7 gave 13a
and 13b in 74 and 72% yield, (eq 5; the mixture of complexes
can also be demetalated to afford a mixture of 13a/b).
Exposure of 6b to thermal cyclization conditions for 20 h
generated two separable regioisomers 10a and 10b. Stirring the
mixture of 10a/b with CuCl2 in EtOH gave a complex mixture
of products (TLC), as expected from our experience with 9a/b.
Consequently 10a and 10b were demetalated separately with
trimethylamine N-oxide to afford dienes 14a and 14b (Scheme
2). We studied the hydrolysis of 14a and 14b separately. While
14b was hydrolyzed quickly by stirring with oxalic acid for 10
min to afford ketone 15 cleanly, under the same conditions 14a
afforded a mixture of several products according to TLC,
among which the major product was not 15; after 24 h under
the same conditions, the TBS group was found to be
completely removed, but still a mixture of products was
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Note
°C 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
water (4 mL), extracted with Et2O (10 mL × 3), and the combined
extract was washed with brine (5 mL × 2), dried (Na2SO4), filtered
and concentrated in vacuo. Flash chromatography (Hex:EA/9:1)
afforded 4b as two isomers (307 mg, 72%) as a yellow oil. Rf = 0.2
obtained. Next we examined the hydrolysis of 14a/b using
aqueous HCl in methanol. Dienol ether 14b was cleanly
hydrolyzed to 15 in 10 min. Under the same conditions, 14a
still afforded a mixture of several products (by TLC) after 15
min reaction time. After adjusting the pH to 11 using NaOH
solution, stirring was continued for 24 h, and 15 was isolated as
the major product. To expedite the overall conversion to the
final enone, the mixture of 14a and 14b was hydrolyzed to 15
in a yield of 67% using this procedure (Scheme 2).
1
(Hex:EA/9:1). H NMR (400 MHz, CDCl3): δ 7.40−7.31 (m, 4H),
7.29−7.20 (m, 2H), 7.18−7.10 (m, 4H), 6.18 (d, J = 13.0 Hz, 1H),
5.82 (d, J = 4.6 Hz, 1H), 5.38−5.34 (m, 2H), 4.84 (ddd, 13.0, 8.1, 7.0
Hz, 1H), 4.52−4.42 (m, 2H), 4.39 (dd, J = 14.0, 7.0 Hz, 1H), 4.21−
4.12 (m, 1H), 3.77 (dd, J = 14.0, 8.1 Hz, 1H), 3.39 (s, 3H), 3.38 (s,
3H), 3.38 (s, 3H), 3.37−3.34 (m, 2H), 3.32 (s, 3H), 1.72−1.55 (m,
3H), 1.19−1.05 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 173.7,
173.5, 151.1, 148.6, 143.8, 143.3, 138.4, 138.4, 129.8, 129.6, 128.5,
128.0, 127.8, 127.4, 102.2, 97.6, 68.9, 68.9, 60.7, 60.5, 59.7, 56.0, 55.9,
55.9, 54.2, 51.1, 46.6, 27.0, 26.8, 24.5. HRMS (EI) calcd for
C21H22FeNO6 [M + H]+ 440.0797, found 440.0796.
EXPERIMENTAL SECTION
■
High Resolution Mass Spectrometry (HRMS). HRMS measure-
ments were made in-house using a magnetic sector instrument. Iron
carbonyl complexes often do not give a molecular ion, owing to facile
loss of one or more CO ligands. However, we have found that
evaporation of solvent from a solution of the iron complex in ethyl
acetate prior to sample introduction overcomes this problem and gives
appropriate molecular ions for most complexes; we do not currently
have an explanation for this observation.
[3-Methoxy-N-(3-oxopropyl)-N-phenylcyclohexa-1,3-
dienecarboxamide]tricarbonyliron (5b). A solution of 4b (178 mg,
0.40 mmol) in dioxane (6 mL) was treated with 2 N HCl (2 mL) at rt
for 1.5 h. Et2O (50 mL) was added, and the solution was washed with
water (10 mL) and brine (10 mL), dried (Na2SO4), filtered and
concentrated in vacuo. Flash chromatography (Hex:EA/4:1) afforded
General Procedure for the Thermally Induced Cyclization.
The appropriate amide was dissolved in freshly distilled n-butyl ether
(0.02 mmol/mL) under Ar in a dried glass round-bottom flask. The
solution was degassed by bubbling with Ar for 10 min and then with
CO for 10 min. The solution was refluxed under a balloon of CO for
8−20 h. The cooled reaction mixture was filtered through Celite and
was concentrated in vacuo. Flash chromatography yielded the desired
products.
General Procedure for Demetalation. Method A: To a solution
of the iron complex in benzene was added trimethylamine oxide (30
equiv). The reaction mixture was stirred for 24 h at rt and then was
filtered through Celite and concentrated in vacuo. Separation by flash
chromatography 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 18−24 h
and then was concentrated in vacuo. After water (4 mL) was added to
the residue, the mixture was extracted with ether (3 mL × 3). The
organic layer was washed with brine, dried (Na2SO4), filtered, and
concentrated in vacuo. The crude products were purified by flash
chromatography.
1
5b (160 mg, 94%) as a yellow oil. Rf = 0.3 (Hex:EA/4:1). H NMR
(400 MHz, CDCl3): δ 9.69 (s, 1H), 7.46−7.37 (m, 2H), 7.35−7.28
(m, 1H), 7.23−7.15 (m, 2H), 5.28 (s, 1H), 4.29−4.19 (m, 1H), 3.71−
3.60 (m, 1H), 3.38 (s, 3H), 3.41−3.36 (m, 1H), 2.84−2.74 (m, 1H),
2.62−2.52 (m, 1H), 1.65−1.55 (m, 1H), 1.14−1.04 (m, 1H). 13C
NMR (100 MHz, CDCl3): δ 200.8, 174.3, 143.4, 138.4, 130.2, 128.1,
128.0, 68.9, 59.9, 56.0, 54.2, 46.6, 42.3, 26.9, 24.4. HRMS (EI) calcd
for C20H20FeNO6 [M + H]+ 426.0640, found 426.0629.
[N-(3-((tert-Butyldimethylsilyl)oxy)allyl)-N-phenylcyclohexa-1,3-
dienecarboxamide]tricarbonyliron (6a). To a solution of aldehyde 5a
(30.0 mg, 76 μmol) and DIPEA (19.6 mg, 152 μmol) in CH2Cl2 (2
mL) at 0 °C under Ar, was added dropwise a solution of TBSOTf
(30.1 mg, 114 μmol) in CH2Cl2 (0.2 mL). After the reaction solution
was stirred at 0 °C for 2 h, it was quenched with sat. sodium
bicarbonate (2 mL), and then extracted with CH2Cl2 (2 mL × 3). The
combined organic extract was washed with brine (2 mL) and dried
over Na2SO4. Flash chromatography (Hex:EA/8:1) afforded 6a as two
isomers (32.4 mg, 84%, E/Z = 7/1) as a yellow oil. Rf = 0.3 (Hex:EA/
[N-(3-Methoxyallyl)-N-phenylcyclohexa-1,3-dienecarboxamide]-
tricarbonyliron (4a). To a mixture of (methoxymethyl)-
triphenylphosphonium chloride (310 mg, 0.91 mmol) in THF (6
mL) under Ar at −78 °C, was added KHMDS (0.5 M in toluene, 2.0
mL, 0.99 mmol). Stirring was continued at this temperature for 1 h,
then a solution of aldehyde 3a (230 mg, 0.60 mmol) in THF (2.0 mL)
was added and the reaction was held at −78 °C 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 water (4 mL), extracted
with Et2O (6 mL × 3), and the combined extract was washed with
brine (3 mL × 2), dried (Na2SO4), filtered and concentrated in vacuo.
Flash chromatography (Hex:EA/8:1) afforded 4a as two isomers (185
mg, 75%) as a yellow oil. Rf = 0.22 (Hex:EA/8:1; Hex = hexanes, EA =
1
8:1). E isomer: H NMR (400 MHz, C6D6): δ 7.11−7.05 (m, 2H),
6.98−6.94 (m, 3H), 6.30 (d, J = 12.0 Hz, 1H), 5.45−5.38 (m, 1H),
5.34 (d, J = 4.4 Hz, 1H), 4.55 (dd, J = 14.0, 7.2 Hz, 1H), 4.30−4.22
(m, 1H), 3.92 (dd, J = 14.0, 8.4 Hz, 1H), 2.61−2.59 (m, 1H), 2.17−
2.10 (m, 1H), 1.56−1.48 (m, 1H), 1.19−1.09 (m, 2H), 0.88 (s, 9H),
0.00 (s, 6H). 13C NMR (100 MHz, C6D6): δ 211.5, 172.0, 145.2,
144.2, 129.6, 127.0, 106.5, 87.0, 83.6, 73.2, 63.1, 49.9, 46.3, 26.1, 15.6,
18.4, −3.4, −5.3. Z isomer: 1H NMR (400 MHz, C6D6): δ 7.11−7.05
(m, 2H), 6.98−6.94 (m, 3H), 6.10 (d, J = 5.6 Hz, 1H), 5.45−5.38 (m,
1H), 5.08−5.03 (m, 1H), 4.75 (dd, J = 14.0, 6.4 Hz, 1H), 4.61−4.57
(m, 1H), 4.29−4.22 (m, 1H), 2.61−2.59 (m, 1H), 2.17−2.10 (m, 1H),
1.56−1.48 (m, 1H), 1.19−1.09 (m, 2H), 0.78 (s, 9H), −0.10 (s, 3H),
−0.16 (s, 3H). 13C NMR (100 MHz, C6D6): δ 211.5, 171.8, 144.8,
141.2, 129.5, 126.9, 106.2, 86.9, 83.5, 73.1, 63.0, 46.3, 25.7, 25.5, 18.2,
−3.4, −5.6. HRMS (EI) calcd for C24H28FeNO5Si [M − CH3]+
494.1086, found 494.1067.
1
ethyl acetate). H NMR (400 MHz, C6D6): δ 7.00−6.96 (m, 5H),
6.90−6.87 (m, 5H), 6.17 (d, J = 12.8 Hz, 1H), 5.48 (d, J = 6.4 Hz,
1H), 5.29−5.26 (m, 2H), 5.02−4.95 (m, 1H), 4.81−4.76 (m, 1H),
4.70−4.65 (m, 1H), 4.49−4.36 (m, 2H), 4.17−4.13 (m, 2H), 3.81 (dd,
J = 14.0, 8.0 Hz, 1H), 3.00 (s, 3H), 2.78 (s, 3H), 2.52 (d, J = 3.6 Hz,
2H), 2.14−2.02 (m, 2H), 1.45−1.39 (m, 2H), 1.12−1.03 (m, 4H). 13C
NMR (100 MHz, C6D6): δ 211.5, 172.1, 171.8, 151.4, 148.7, 144.8,
144.2, 129.7, 129.5, 127.1, 126.9, 102.7, 97.9, 86.9, 83.6, 83.5, 73.3,
73.0, 63.2, 63.1, 59.0, 55.3, 50.7, 46.3, 26.2, 26.1, 25.6, 25.5. HRMS
(EI) calcd for C20H20FeNO5 [M + H]+ 410.0691, found 410.0679.
[3-Methoxy-N-(3-methoxyallyl)-N-phenylcyclohexa-1,3-
dienecarboxamide]tricarbonyliron (4b). To a mixture of
(methoxymethyl)triphenylphosphonium chloride (617 mg, 1.8
mmol) in THF (10 mL) under Ar at −78 °C was added KHMDS
(0.5 M in toluene, 4.6 mL, 2.3 mmol). Stirring was continued at this
temperature for 1 h, then a solution of aldehyde 3b (400 mg, 0.97
mmol) in THF (2.0 mL) was added and the reaction was held at −78
[N-(3-((tert-Butyldimethylsilyl)oxy)allyl)-3-methoxy-N-phenylcy-
clohexa-1,3-dienecarboxamide]tricarbonyliron (6b). To a solution
of aldehyde 5b (49.4 mg, 91 μmol) and DIPEA (23.6 mg, 183 μmol)
in CH2Cl2 (3 mL) at 0 °C under Ar, was added dropwise a solution of
TBSOTf (30.1 mg, 114 μmol) in CH2Cl2 (0.2 mL). After the reaction
solution was stirred at 0 °C for 2 h, it was quenched with sat. sodium
bicarbonate (2 mL), and then extracted with CH2Cl2 (2 mL × 3). The
combined organic extract was washed with brine (2 mL) and dried
over Na2SO4. Flash chromatography (Hex:EA/8:1) afforded 6b as two
isomers (39.3 mg, 80%, E/Z = 5.5/1) as a yellow oil. Rf = 0.33
1
(Hex:EA/8:1). E isomer: H NMR (400 MHz, CDCl3): δ 7.45−7.39
(m, 2H), 7.34−7.30 (m, 1H), 7.20−7.15 (m, 2H), 6.13 (d, J = 12.0
Hz, 1H), 5.43 (s, 1H), 5.07 (ddd, J = 12.0, 8.3, 7.0 Hz, 1H), 4.43 (dd,
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Note
14.1, 7.0 Hz, 1H), 3.89 (dd, 14.1, 8.3 Hz, 1H), 3.46 (s, 3H), 3.44−3.40
(m, 1H), 1.75−1.62 (m, 3H), 1.22−1.11 (m, 1H), 0.84 (s, 9H), 0.04
(s, 6H). 13C NMR (100 MHz, CDCl3): δ 173.6, 145.1, 143.3, 138.5,
129.9, 128.7, 127.7, 106.0, 69.1, 56.0, 54.4, 50.4, 27.0, 25.9, 24.7, 18.6,
−5.0, −5.0. Z isomer: 1H NMR (400 MHz, CDCl3): δ 7.41−7.36 (m,
2H), 7.31−7.28 (m, 1H), 7.24−7.20 (m, 2H), 6.20 (d, J = 5.7 Hz,
1H), 5.30 (s, 1H), 4.73−4.66 (m, 1H), 4.52−4.45 (m, 1H), 4.30 (dd,
14.4, 8.0 Hz, 1H), 3.46 (s, 3H), 3.44−3.40 (m, 1H), 1.75−1.62 (m,
3H), 1.22−1.11 (m, 1H), 0.74 (s, 9H), −0.01 (s, 3H), −0.08 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 173.8, 144.0, 141.5, 138.5, 129.7,
(dd, J = 3.2, 2.0 Hz, 1H), 2.87 (d, J = 6.0 Hz, 1H), 2.25−2.21 (m, 1H),
2.03 and 1.91 (ABX, J = 15.2, 2.0 Hz, 2H), 0.84 (s, 9H), 0.06 (s, 3H),
0.03 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 211.8, 176.2, 139.7,
128.7, 124.2, 119.2, 86.7, 84.9, 61.8, 60.9, 59.6, 51.8, 48.1, 46.5, 40.1,
25.8, 18.1, −5.5, −5.6. HRMS (EI) calcd for C24H28FeNO5Si [M−
CH3]+ 494.1086, found 494.1084.
[4-(((tert-Butyldimethylsilyl)oxy)methyl)-9-methoxy-2-phenyl-2-
azaspiro[4.5]deca-6,8-dien-1-one]tricarbonyliron (10a) and [4-
(((tert-butyldimethylsilyl)oxy)methyl)-7-methoxy-2-phenyl-2-
azaspiro[4.5]deca-6,8-dien-1-one]tricarbonyliron (10b). According
to the general procedure for thermally induced cyclization, a solution
of 6b (40 mg, 74 μmol) in n-Bu2O (5 mL) was heated at 142 °C
under CO for 20 h. Flash chromatography (Hex:EA/15:1 then 8:1)
afforded two isomers 10a (14 mg, 35%)as a crystalline solid and 10b
(15.5 mg, 39%) as an oil. 10a: Rf = 0.23 (Hex:EA/12:1). Mp: 142−
144 °C. 1H NMR (400 MHz, (CD3)2O): δ 7.84−7.79 (m, 2H), 7.43−
7.36 (m, 2H), 7.17−7.10 (m, 1H), 5.69 (d, J = 4.7 Hz, 1H), 5.20 (dd, J
= 6.3, 4.7 Hz, 1H), 4.37 (dd, J = 10.3, 7.2 Hz, 1H), 3.98 (dd, J = 10.7,
4.0 Hz, 1H), 3.91 (dd, J = 10.7, 2.8 Hz, 1H), 3.75 (d, J = 10.3 Hz, 1H),
3.62 (s, 3H), 3.10 (dd, J = 6.3, 1.2 Hz, 1H), 2.66 (d, J = 15.4 Hz, 1H),
2.54−2.49 (m, 1H), 2.29 (d, J = 15.4 Hz, 1H), 0.80 (s, 9H), 0.08 (s,
3H), 0.00 (s, 3H). 13C NMR (100 MHz, (CD3)2O): δ 213.2, 175.5,
140.7, 128.6, 123.6, 120.2, 119.0, 79.6, 74.0, 63.0, 62.0, 56.1, 50.4, 49.5,
43.5, 34.3, 25.3, 17.8, −6.3, −6.4. HRMS (EI) calcd for MH+
(C26H34FeNO6Si) 540.1505, found 540.1487. 10b: Rf = 0.26
128.3, 127.6, 105.3, 69.1, 56.0, 54.4, 46.6, 27.1, 25.8, 24.7, 18.3, −5.2,
−5.3. HRMS (EI) calcd for C26H34FeNO6Si [M + H]+ 540.1505,
found 540.1512.
[4-(Methoxymethyl)-2-phenyl-2-azaspiro[4.5]deca-6,8-dien-1-
one]tricarbonyliron (7a and 7b). According to the general procedure
for thermally induced cyclization, a solution of 4a (35.5 mg, 86.7
μmol) in n-Bu2O (4.5 mL) was heated at 142 °C under CO for 8 h.
Flash chromatography (Hex:EA/8:1) afforded a mixture of two
isomers 7a and 7b (27.7 mg, 78%) as a yellow oil. Rf = 0.23 (Hex:EA/
1
8:1). H NMR (400 MHz, CDCl3): δ 7.67−7.60 (m, 4H), 7.37−7.32
(m, 4H), 7.14−7.10 (m, 2H), 5.59−5.56 (m, 2H), 5.51−4.92 (m, 1H),
5.32−5.30 (m, 1H), 4.05 (dd, J = 4.0, 3.2 Hz, 1H), 3.81−3.70 (m,
4H), 3.54 (dd, J = 4.2, 4.2 Hz, 1H), 3.46−3.48 (m, 2H), 3.38 (s, 3H),
3.30−3.23 (m, 2H), 3.23 (s, 3H), 3.01 (dd, J = 2.4, 1.2 Hz, 1H), 2.78
(dd, J = 6.8, 1.2 Hz, 1H), 2.05−2.02 (m, 1H), 1.94−1.91 (m, 1H),
2.10−1.90 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 211.6, 211.5,
176.2, 176.1, 139.8, 139.6, 128.8, 128.7, 124.4, 124.3, 119.4, 119.3,
88.7, 86.9, 84.6, 82.1, 71.3, 71.0, 63.8, 63.3, 61.1, 59.4, 59.1, 59.0, 51.7,
50.9, 48.7, 48.1, 44.5, 41.7, 40.0, 32.2. HRMS (EI) calcd for
C20H20FeNO5 [M + H]+ 410.0691, found 410.0675.
1
Hex:EA/8:1). H NMR (400 MHz, CDCl3): δ 7.66−7.62 (m, 2H),
7.35−7.29 (m, 2H), 7.12−7.07 (m, 1H), 5.24−5.21 (m, 1H), 3.93 (dd,
J = 10.2, 3.9 Hz, 1H), 3.86 (dd, J = 10.2, 6.8 Hz, 1H), 3.82 (dd, J =
10.2, 6.5 Hz, 1H), 3.74 (s, 3H), 3.72 (dd, J = 10.2, 1.8 Hz, 1H), 3.16
(d, J = 2.1 Hz, 1H), 2.74−2.70 (m, 1H), 2.30−2.24 (m, 1H), 1.92−
1.87 (m, 1H), 1.74 (dd, J = 14.8, 3.2 Hz, 1H), 0.83 (s, 9H), 0.06 (s,
3H), 0.02 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 176.8, 141.7,
140.0, 129.0, 124.4, 119.4, 67.8, 62.3, 55.4, 53.8, 48.8, 48.2, 46.3, 40.6,
26.1, 18.4, −5.2, −5.3. HRMS (EI) calcd for C26H34FeNO6Si [M +
H]+ 540.1505, found 540.1497.
[9-Methoxy-4-(methoxymethyl)-2-phenyl-2-azaspiro[4.5]deca-
6,8-dien-1-one]tricarbonyliron (8a) and [7-methoxy-4-(methoxy-
methyl)-2-phenyl-2-azaspiro[4.5]deca-6,8-dien-1-one]tri- carbony-
liron (8b). According to the general procedure for thermally induced
cyclization, a solution of 4b (85.1 mg, 0.19 mmol) in n-Bu2O (10 mL)
was heated at 142 °C under CO for 20 h. Flash chromatography
(Hex:EA/10:1) afforded mixture of 8a and 8b (65 mg, 76%) as a
4-(Methoxymethyl)-2-phenyl-2-azaspiro[4.5]deca-6,8-dien-1-one
(11a and 11b). According to method B of the general procedure for
demetalation, the mixture of 7a and 7b (31 mg, 75.8 μmol) was stirred
with sat. CuCl2 solution in EtOH (2.05 mL) for 18 h. The crude
product was purified by flash chromatography (Hex:EA/5:1) to afford
a mixture of two isomers (15.1 mg, 74%) as an oil. Rf = 0.40 (Hex:EA/
1
yellow oil. Rf = 0.25 (Hex:EA/10:1). H NMR (400 MHz, CDCl3): δ
7.66−7.60 (m, 4H), 7.37−7.28 (m, 4H), 7.14−7.07 (m, 2H), 5.50 (d, J
= 4.5 Hz), 5.21−5.18 (m, 1H), 4.99 (dd, J = 6.2, 4.5 Hz, 1H), 4.04
(dd, J = 10.2, 6.8 Hz, 1H), 3.78−3.74 (m, 2H), 3.73 (s, 3H), 3.72−
3.67 (m, 2H), 3.53 (s, 3H), 3.51−3.44 (m, 2H), 3.39−3.36 (m, 1H),
3.36 (s, 3H), 3.27 (s, 3H), 3.00 (d, J = 1.9 Hz, 1H), 2.75−2.70 (m,
2H), 2.56−2.48 (m, 1H), 2.45 (d, J = 15.1 Hz, 1H), 2.42−2.35 (m,
1H), 2.20 (d, J = 15.1 Hz, 1H), 1.89 (dd, J = 14.8, 1.7 Hz, 1H), 1.74
(dd, J = 14.8, 3.2 Hz, 1H) . 13C NMR (100 MHz, CDCl3): δ 212.6,
176.7, 176.0, 141.4, 139.9, 129.1, 129.1, 124.6, 119.7, 119.6, 119.3,
79.7, 73.4, 71.8, 71.4, 67.5, 60.3, 59.4, 56.7, 55.3, 53.7, 53.7, 50.7, 49.1,
48.8, 48.0, 44.4, 41.9, 40.4, 34.0. HRMS (EI) calcd for C21H22FeNO6
[M + H]+ 440.0797, found 440.0789.
1
5:1). H NMR (400 MHz, CDCl3): δ 7.73−7.69 (m, 4H), 7.42−7.28
(m, 4H), 7.19−7.15 (m, 2H), 6.16 (m, 2H), 6.00−5.95 (m, 2H),
5.90−5.88 (m, 1H), 5.82−5.81 (m, 1H), 5.74 (dt, J = 11.2, 0.8 Hz,
1H), 5.59 (dt, J = 10.8, 0.8 Hz, 1H), 3.95−3.88 (m, 2H), 3.74−3.30
(m, 2H), 3.63−3.57 (m, 2H), 3.46−3.41 (m, 2H), 3.46−3.41 (m, 2H),
3.36 (s, 3H), 3.34 (s, 3H), 3.04 (dt, J = 18.0, 2.8 Hz, 1H), 2.68 (dt, J =
18.0, 6.0 Hz, 1H), 2.61−2.57 (m, 1H), 2.56−2.48 (m, 1H), 2.41 (dd, J
= 18.0, 5.6 Hz, 1H), 2.31 (dd, J = 18.0, 6.0 Hz, 1H). 13C NMR (100
MHz, CDCl3): δ 177.4, 177.0, 139.6, 139.5, 128.9, 127.0, 126.7, 125.6,
125.1, 124.5, 124.2, 123.6, 123.0, 119.7, 119.6, 72.0, 71.9, 59.1, 59.0,
49.0, 48.6, 48.3, 43.5, 42.5, 31.7, 26.0. HRMS (EI) calcd for
C17H19NO2 [M]+ 269.1416, found 269.1418.
[4-(((tert-Butyldimethylsilyl)oxy)methyl)-2-phenyl-2-azaspiro-
[4.5]deca-6,8-dien-1-one]tricarbonyliron (9a and 9b). According to
the general procedure for thermally induced cyclization, a solution of
6a (50 mg, 0.10 mmol) in n-Bu2O (5 mL) was heated at 142 °C under
CO for 8 h. Gravity column chromatography (Hex:EA/12:1) afforded
individual isomers 9a (17.5 mg, 35%) as a crystalline solid and 9b
(18.1 mg, 36%) as an oil. 9a: Rf = 0.22 Hex:EA/12:1). Mp: 132−135
4-(Methoxymethyl)-2-phenyl-2-azaspiro[4.5]dec-8-ene-1,7-dione
(12). According to method B of the general procedure for
demetalation, the mixture of 8a and 8b (30.5 mg, 68.5 μmol) was
stirred with sat. CuCl2 solution in EtOH (2 mL) for 22 h. Flash
chromatography (Hex:EA/2:1) afforded 12 (15 mg, 77%). Rf = 0.30
1
°C. H NMR (400 MHz, CDCl3): δ 7.65 (dd, J = 8.8, 1.2 Hz, 2H),
1
7.36−7.31 (m, 2H), 7.13−7.09 (m, 1H), 5.56−5.54 (m, 1H), 5.33−
5.30 (m, 1H), 4.11 (dd, J = 4.2, 4.0 Hz, 1H), 3.70−3.62 (m, 3H),
3.43−3.39 (m, 1H), 3.00 (dd, J = 6.0, 1.2 Hz, 1H), 2.38−2.34 (m,
1H), 2.11 and 2.04 (ABX, J = 16.0, 2.4 Hz, 2H), 0.76 (s, 9H), −0.03
(s, 3H), −0.08 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 211.6, 176.3,
139.9, 128.7, 124.0, 119.1, 88.7, 82.2, 64.2, 63.5, 62.2, 50.7, 49.1, 43.5,
32.4, 25.6, 17.9, −5.7, −5.8. HRMS (EI) calcd for [M+H]+
(C25H32FeNO51Si) 510.1399, found, 510.1363. 9b: Rf = 0.20
Hex:EA/12:1). H NMR (400 MHz, CDCl3): δ 7.61 (d, J = 7.6 Hz,
2H), 7.34 (dd, J = 8.4, 7.6 Hz, 2H), 7.11 (dd, J = 7.6, 7.2 Hz, 1H),
5.62−5.59 (m, 1H), 5.50 (dd, J = 5.6, 5.2 Hz, 1H), 3.96 (dd, J = 10.4,
4.0 Hz, 1H), 3.86−3.80 (m, 2H), 3.71 (dd, J = 10.0, 3.2 Hz, 1H), 3.22
(Hex:EA/2:1). H NMR (400 MHz, CDCl3): δ 7.68−7.62 (m, 2H),
7.42−7.35 (m, 2H), 7.20−7.14 (m, 2H), 6.94 (ddd, J = 10.2, 5.4, 2.8
Hz, 1H), 6.17−6.13 (m, 1H), 3.94 (dd, J = 10.3, 7.2 Hz, 1H), 3.70
(dd, J = 10.3, 4.1 Hz, 1H), 3.43 (dd, J = 9.4, 5.4 Hz, 1H), 3.36 (dd, J =
9.4, 1.8 Hz, 1H), 3.28 (s, 3H), 2.89−2.81 (m, 2H), 2.59−2.42 (m,
2H). 13C NMR (100 MHz, CDCl3): δ 197.2, 174.7, 146.8, 139.3,
130.1, 129.2, 129.1, 125.1, 120.0, 71.7, 59.2, 50.3, 48.6, 40.9, 40.7, 34.1.
HRMS (EI) calcd for C17H19NO3 [M]+ 285.1365, found 285.1363.
[4-(((tert-Butyldimethylsilyl)oxy)methyl)-2-phenyl-2-azaspiro-
[4.5]deca-6,8-dien-1-one]tricarbonyliron (13a and 13b). According
to method B of the general procedure for demetalation, 9a (17 mg,
33.4 μmol) and 9b (18 mg, 35.3 μmol) were each stirred separately
8838
dx.doi.org/10.1021/jo301721d | J. Org. Chem. 2012, 77, 8835−8839

The Journal of Organic Chemistry
Note
with Me3NO (30 equiv) in benzene (1 mL) at rt for 24 h. Flash
chromatography (Hex:EA/10:1 and 12:1) afforded 13a (9.1 mg, 74%)
and 13b (9.4 mg, 72%), respectively, each as a film. 13a: Rf = 0.25
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
(Hex:EA/10:1). H NMR (400 MHz, CDCl3): δ 7.68−7.63 (m, 2H),
7.37−7.32 (m, 2H), 7.15−7.09 (m, 1H), 6.09 (dd, J = 9.5, 4.9 Hz,
1H), 5.95−5.90 (m, 1H), 5.80−5.75 (m, 1H), 5.71−5.67 (m, 1H),
3.86 (dd, J = 9.8, 7.4 Hz, 1H), 3.78 (dd, J = 10.3, 4.2 Hz, 1H), 3.67
(dd, J = 9.8, 7.2 Hz, 1H), 3.61 (dd, J = 10.3, 8.4 Hz, 1H), 2.68−2.60
(m, 1H), 2.42−2.31 (m, 2H), 0.84 (s, 9H), 0.02 (s, 3H), 0.00 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 177.7, 139.8, 129.0, 127.4, 125.6,
AUTHOR INFORMATION
Corresponding Author
*ajp4@case.edu
■
124.7, 124.6, 123.8, 119.8, 63.0, 48.7, 48.5, 45.9, 26.0, 26.0, 18.4, −5.2,
−5.3. HRMS (EI) calcd for M+ (C22H31NO2Si) 369.2124, found,
369.2119. 13b: Rf = 0.22 (Hex:EA/12:1). 1H NMR (400 MHz,
CDCl3): δ 7.71−7.67 (m, 2H), 7.40−7.34 (m, 2H), 7.16−7.12 (m,
1H), 6.12 (dd, J = 9.7, 5.1 Hz, 1H), 5.98−5.93 (m, 1H), 5.86−5.80
(m, 1H), 5.66−5.62 (m, 1H), 3.91 (dd, J = 10.0, 7.5 Hz, 1H), 3.78
(dd, J = 10.3, 4.2 Hz, 1H), 3.69 (dd, J = 10.0, 5.4 Hz, 1H), 3.65 (dd, J
= 10.3, 8.0 Hz, 1H), 2.93 (dt, J = 17.8, 3.9 Hz, 1H), 2.53−2.46 (m,
1H), 2.28 (dd, J = 17.8, 5.6 Hz, 1H), 0.84 (s, 9H), 0.02 (s, 3H), 0.00
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 177.7, 140.0, 129.1, 128.7,
126.8, 125.1, 124.7, 124.0, 123.8, 119.9, 62.8, 49.2, 48.7, 43.7, 32.0,
26.1, 18.4, −5.1, −5.2. HRMS (EI) calcd for C22H31NO2Si [M]+
369.2124, found 369.2114.
4-(((tert-Butyldimethylsilyl)oxy)methyl)-9-methoxy-2-phenyl-2-
azaspiro[4.5]deca-6,8-dien-1-one (14a) and 4-(((tert-
Butyldimethylsilyl)oxy)methyl)-7-methoxy-2-phenyl-2-azas-
piro[4.5]-deca-6,8-dien-1-one (14b). According to method B of the
general procedure for demetalation, 10a (13 mg, 24.1 μmol) and 10b
(14 mg, 26.0 μmol) were each stirred separately with Me3NO (30
equiv.) in benzene (1 mL) at rt for 24 h. Flash chromatography
(Hex:EA/10:1 and 12:1) afforded 14a (6.7 mg, 70%) and 14b (7.8
mg, 75%), respectively, each as a film. 14a: Rf = 0.25 (Hex:EA/10:1).
1H NMR (400 MHz, CDCl3): δ 7.70−7.65 (m, 2H), 7.40−7.33 (m,
2H), 7.16−7.10 (m, 1H), 6.08 (dd, J = 9.4, 6.1 Hz, 1H), 5.37 (d, J =
9.4 Hz, 1H), 4.96 (dd, J = 6.1, 2.2 Hz, 1H), 3.90 (dd, J = 9.8, 7.2 Hz,
1H), 3.82 (dd, J = 10.4, 4.2 Hz, 1H), 3.68 (dd, J = 9.8, 5.9 Hz, 1H),
3.65−3.59 (m, 1H), 3.61 (s, 3H), 2.89−2.82 (m, 1H), 2.41−2.28 (m,
2H), 0.85 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 177.0, 157.5, 140.0, 129.1, 126.3, 124.7, 120.2, 120.0, 92.0,
62.4, 55.3, 50.6, 48.9, 45.4, 30.2, 26.2, 18.5, −5.1, −5.2. HRMS (EI)
calcd for M+ (C23H331NO3Si) 399.2230, found, 399.2226. 14b: Rf =
0.22 (Hex:EA/12:1). H NMR (400 MHz, CDCl3): δ 7.74−7.68 (m,
2H), 7.41−7.34 (m, 2H), 7.17−7.11 (m, 1H), 5.94−5.88 (m, 1H),
5.85−5.80 (m, 1H), 4.51 (s, 1H), 3.90 (dd, J = 10.0, 4.4 Hz, 1H), 3.77
(dd, J = 10.0, 7.5 Hz, 1H), 3.68 (dd, J = 10.0, 4.6 Hz, 1H), 3.66 (dd, J
= 10.0, 2.2 Hz, 1H), 3.58 (s, 3H), 2.89−2.82 (m, 1H), 2.49−2.42 (m,
1H), 2.27 (dd, 17.7, 5.6 Hz, 1H), 0.84 (s, 9H), 0.02 (s, 3H), −0.01 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 178.1, 155.4, 140.1, 129.1,
127.8, 124.6, 124.0, 119.8, 90.6, 63.1, 54.6, 49.4, 49.1, 43.8, 32.6, 26.1,
18.5, −5.1, −5.2. HRMS (EI) calcd for C23H33NO3Si [M]+ 399.2230,
found 399.2228.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Science Foundation (CHE-
0743234) and Case Western Reserve University for financial
support of this research.
REFERENCES
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4-(((tert-Butyldimethylsilyl)oxy)methyl)-2-phenyl-2-azaspiro[4.5]-
dec-8-ene-1,7-dione (15). To a solution of a 1:1 mixture of 14a and
14b (10.1 mg, 25.3 μmol) in MeOH (1 mL) were added 5 drops of 1
M HCl and the solution was stirred for 15 min. Aqueous NaOH (0.1
M) was added to adjust the pH to 11 and stirring was continued for 24
h. The reaction mixture was extracted with ether (3 mL × 3), and the
combined organic layers were washed with brine (2 mL) and dried
over Na2SO4. Flash chromatography (Hex:EA/4:1) afforded 15 (6.5
1
mg, 67%) as a film. Rf = 0.22 (Hex:EA/4:1). H NMR (400 MHz,
CDCl3): δ 7.69−7.64 (m, 2H), 7.41−7.34 (m, 2H), 7.19−7.13 (m,
1H), 6.96−6.89 (m, 1H), 6.18−6.12 (m, 1H), 3.96 (dd, J = 10.1, 7.4
Hz, 1H), 3.73−3.66 (m, 2H), 3.61 (dd, J = 10.1, 6.5 Hz, 1H), 2.90 (d,
J = 16.8 Hz, 1H), 2.83−2.75 (m, 1H), 2.66 (d, J = 16.8 Hz, 1H), 2.51−
2.36 (m, 2H), 0.80 (s, 9H), 0.02 (s, 3H), −0.03 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 197.7, 174.9, 146.7, 130.3, 129.2, 125.0, 119.9,
62.7, 50.3, 48.9, 42.3, 40.8, 34.3, 26.0, 18.4, −5.3, −5.3. HRMS (EI)
calcd for C22H31NO3Si [M]+ 385.2073, found 385.2071.
8839
dx.doi.org/10.1021/jo301721d | J. Org. Chem. 2012, 77, 8835−8839