Electronic control of product distribution in the [5+5]-coupling of ortho-alkynylbenzaldehyde derivatives and γ,δ-unsaturated carbene complexes

Article abstract of DOI:10.1016/j.tet.2010.04.117

The coupling of highly oxygenated ortho-alkynylbenzaldehyde derivatives with γ,δ-carbene complexes was evaluated systematically. In all of the electron-rich systems investigated the exclusive product of the reaction is the dihydrophenanthrene derivative.

Full text of DOI:10.1016/j.tet.2010.04.117

Tetrahedron 66 (2010) 4954e4960
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Electronic control of product distribution in the [5þ5]-coupling of ortho-
alkynylbenzaldehyde derivatives and
g
,
d-unsaturated carbene complexes
*
Alejandro Camacho-Davila, Lalith S.R. Gamage, Zhipeng Wang, James W. Herndon
Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM 88003, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The coupling of highly oxygenated ortho-alkynylbenzaldehyde derivatives with g,d-carbene complexes
Received 29 March 2010
Received in revised form 24 April 2010
Accepted 26 April 2010
was evaluated systematically. In all of the electron-rich systems investigated the exclusive product of
the reaction is the dihydrophenanthrene derivative. Only the extremely electron-withdrawing meth-
anesulfonate group can prevent this process from occurring. The use of the base additive collidine
resulted in a surprising yield enhancement but no other discernable effect on the course of the reaction.
Dihydrophenanthrene formation was attributed to rapid dehydration after the opening of a benzo-
oxanorbornene intermediate.
Available online 22 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
results in the direct synthesis of phenanthrenoid ring systems
(e.g., 5, 6) in a process where two of the three rings of the
phenanthrene system are produced in a single reaction.
15
Polycyclic aromatic hydrocarbons1 have tremendous applica-
tions in materials science and medicinal chemistry. Polycyclic aro-
matic rings are frequently employed as organic conductors and
semiconductors,2 serve as the core ring structure for several me-
dicinally important compounds,3 and are useful as fluorescent
probes for biological studies.4 Many polycyclic aromatics derived
from combustion are carcinogenic and prevalent in the environ-
ment, and chemical derivatives are necessary for studies of their
mechanisms of mutagenesis as well as that of their metabolites.5
Phenanthrenes are among the simplest polycyclic aromatics. The
most notable medicinally important phenanthrenoids are the phe-
nanthroindolizidine and phenanthroquinolizidine alkaloids,6 the
aporphine alkaloids,7 and abietane and kaurane diterpenoids.8
Phenanthrenoid ring construction9 is most commonly achieved
using precursors where twoout of the three rings are intact followed
by a cyclization or annulation event. Common approaches to the
construction of the phenanthrenoids include electrocyclizations of
naphthylcyclobutenones,10 naphthyl Fischer carbene complexe
alkyne couplings,11 cyclizations of naphthylvinylketene pre-
cursors,12 cis stilbene cyclizations,13 and ring closing metatheses.14
A unique approach to phenanthrenoid ring systems where two of
the three rings are constructed in a single operation is the highlight
of the studies in this manuscript.
Hydroxyphenanthrenone 5 is formed as a single diastereomer
in a complex tandem process involving the formation of an iso-
benzofuran (3), followed by exo-selective16 intramolecular Dielse
Alder reaction (yielding benzo-oxanorbornene 4), followed by
opening of the benzo-oxanorbornene ring system and hydrolysis.
The DielseAlder step is generally more successful for chromium-
generated isobenzofurans compared to acid-generated iso-
benzofurans.17 In most of the cases examined, hydroxyphenan-
threnones of general structure
5
were produced. The
dihydrophenanthrenone ring systems (6) could be produced after
treatment of the crude reaction mixtures with strong acid. In
a recent total synthesis of antofine, a dihydrophenanthrene de-
rivative (8) was formed directly from the coupling of carbene
complex 2 and alkynylbenzoyl derivative 7.18 This compound was
obtained cleanly after a single chromatography without any acid
treatment. Since dihydrophenanthrene formation is likely related
to the presence of the electron-donating methoxy groups, a more
systematic investigation of this reaction pathway was
undertaken.
2. Results and discussion
The coupling of 2-alkynylbenzoyl derivatives (e.g., 1,
The general synthetic routes to alkyne-carbonyl compounds
from commercially available materials are depicted below in
Schemes 2e4 and involve Sonogashira coupling of trimethylsilyl-
Scheme 1) with
g,d-unsaturated Fischer carbene complexes (2)
acetylene with
a suitable benzaldehyde derivative featuring
a leaving group in the ortho-position as the key step. The precursor
to alkyne-aldehyde 1a (iodide 10) was obtained through ortho
* Corresponding author. Tel.: þ1 575 646 2487; fax: þ1 575 646 2649; e-mail
address: jherndon@nmsu.edu (J.W. Herndon).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.117

A. Camacho-Davila et al. / Tetrahedron 66 (2010) 4954e4960
4955
OMe
R1
OMe
AcO
Cr(CO)5
1. NaNO2 / HCl
2. KI
1. HNO3
HO
NH2
MeO
+
2. FeSO4
NH4OH
/
R2
CHO
CHO
87%
11
2
12
O
75%
1
OMe
OMe
OMe
TMS
R1
R1
OMe
1. Ac2O / py
AcO
HO
I
2. Et3N / Pd cat. &
O
O
H
CHO
CHO
TMS
65%
1c
13
R2
4
R2
3
1. MsCl / py
Et3N / Pd
cat. &
O
O
2. Et3N / Pd cat. &
R1
R1
TMS
74%
TMS
HCl
99%
OMe
H
H
OMe
TMS
MsO
1d
TMS
6
R2 OH
R2
1 = H in 6 if R1
TMS in 1
HO
5
CHO
R
=
1b
CHO
Scheme 3.
TMS
COOMe
OMe
MeO
TMS
1. Tf2O / py
MeO
OH
MeO
N
MeO
MeO
MeO
2. E3N / Pd cat. &
O
CHO
CHO
+
7
TMS
45%
14
1e
COOMe
N
Cr(CO)5
8
MeO
2
Et3N / Pd cat. &
TMS
MeO
MeO
Br
Scheme 1.
CHO
90%
15
1. MeOH / H+
OMe
TMS
TMS
2. n-BuLi, then I2
MeO
MeO
MeO
MeO
MeO
1. MeLi
3. H3O+
71%
Me
OMe
OMe
2. PCC
82%
9
CHO
1g
O
1f
Scheme 4.
OMe
TMS
OMe
TMS
Pd Cat. / Et3N
MeO
MeO
10
I
unexpected since steric strain between the methoxy and trime-
thylsilyl groups is expected to be quite severe in compounds 17aed.
The reaction employing acetate-protected derivative 1c (entry 3) led
primarily to the desilylated compound 16c, however in several ex-
perimental runs varying amounts of the silyl-retained compound 17c
were observed. The hydroxyphenanthrenone derivative 5d (entry 4)
was obtained from the reaction employing the methanesulfonyloxy
derivative 1d. The yield of this latter process was significantly im-
proved if the reaction was conducted using water as a cosolvent. The
observed dihydrophenanthrene formation is likely due to activation
of the C9eO bond by the electron-donating methoxy group in the
para-position and could likely involve para-quinonemethide-like in-
termediates during the dehydration process (see Scheme 5). Entries
1e4 represent a systematic variation in the electron-donating ability
of the C8-activating substituent. The methoxy (entry 1), hydroxyl
(entry 2), and the less electron-donating acetoxy groups (entry 3) all
result in the dihydrophenanthrenes. Only the severely electron-
withdrawing methanesulfonate group20 (entry 4) results in the hy-
droxyl-group retained product, 5d. In one case (entry 7) the crude
reaction mixture was examined and a product consistent with allyl-
silane/enol ether 18g was observed, however all attempts to
CHO
CHO
99%
1a
Scheme 2.
metallation/iodination of veratraldehyde dimethyl acetal (9)
(Scheme 2). Halide precursors to 1bed were obtained from
2-iodovanillin, which was obtained from vanillin through a known
multistep sequence (Scheme 3).19 Other derivatives were prepared
according to the routes depicted in Scheme 4. Monomethoxy de-
rivative 1e was prepared from commercially available 2-hydroxy-4-
methoxybenzaldehyde. Alkyne-carbonyl compounds 1feg were
prepared from commercially available 6-bromoveratraldehyde.
The aromatic ring oxygenated alkynylbenzaldehyde and alkyny-
lacetophenone derivatives were subjected to reaction with carbene
complex 2; the results are depicted in Table 1. In all cases except for
entries 2 and 4, the exclusive product after chromatographic purifi-
cation was dihydrophenanthrene 16, which results from net de-
hydration and protiodesilylation. Exclusive formation of the silyl-
retained product 17b (entry 2) was observed in the reaction
employing the unprotected phenol 1b. This observation is somewhat

4956
A. Camacho-Davila et al. / Tetrahedron 66 (2010) 4954e4960
Table 1
Synthesis of dihydrophenanthrenes (16e18) through coupling of ortho-alkynylbenzoyl derivatives (1) with Fischer carbene complex 2
Entry
Alkyne-carbonyl cmpd
Product(s)
OMe
Yield (%)
OMe
MeO
TMS
1a
OMe
1
58
MeO
HO
CHO
16a
OMe
OMe
TMS
TMS
MeO
HO
2
3
65
1b
CHO
17b
OMe
OMe
AcO
TMS
OMe
63a
AcO
1c
CHO
16c
O
TMS
MeO
OMe
MsO
TMS
MsO
4
52 (72 in 19:1 dioxane/water)
H
1d
CHO
5d
OH
OMe
TMS
MeO
5
57
MeO
CHO
1e
16e
OMe
TMS
MeO
6
60
MeO
MeO
MeO
CHO
1f
16f
OMe
TMS
MeO
MeO
MeO
MeO
7
40 (92 in 9:1 dioxane/collidine)
Me
O
16g
1g
Me
a
In some experimental runs variable quantities of silylated compound 17c were observed.

A. Camacho-Davila et al. / Tetrahedron 66 (2010) 4954e4960
4957
Cr(CO)5
OMe
4a
OMe
H
OMe
TMS
TMS
MeO
TMS
TMS
H+
MeO
MeO
2
4a
MeO
MeO
O
MeO
MeO
H
H
O
O
H
9
O
R
9
R
4e
4g
Me
20
1g
Me
Carbocation
Formation
OMe
OH
OMe
TMS
TMS
OMe
OMe
TMS
TMS
H+
MeO
MeO
MeO
MeO
MeO
MeO
Vs
OH
H
H
Me
19g
Me
18g
OH
R
R
22
21
OMe
MeO
MeO
ΔE (R = H)
ΔE (R = Me)
20 to 21 - +1.2
20 to 22 - +19.8
21 to 22 - +18.6
20 to 21 - +1.9
20 to 22 - +15.9
21 to 22 - +14.0
16g
Me
Scheme 5.
(all values in kcal/mol)
Scheme 6.
chromatographically purify this compound resulted in its conversion
to the desilylated dihydrophenanthrene 16g.
Interesting proton NMR properties were noted for some of the
products in Table 1. For the enol ether protons of 16, a simple
PascualeMeiereSimon calculation21 suggests that this proton
In order to gain further insight into the reaction pathway, the
conversion of the benzo-oxanorbornene intermediate to the final
product was studied computationally (DFT-B3LYP, 6-31G ). The
*
should have a chemical shift of about
drophenanthrene examples in the table. This proton occurs at
7.24 and 7.11 in adducts 16a and 16c, respectively, however
occurs at 6.1e6.2 in all of the other derivatives of 16 in the table.
The chemical shift of compounds 16a and 16f was calculated
(DFT-B3LYP, 6-31G ) and it was found that the chemical shift of
16a is predicted to be greater by 0.61, perhaps due to the
d
5.6 for all of the dihy-
simplest adduct 4e was selected for this study to minimize times
required for optimization. Protonation of the benzo-oxanorbornene
intermediate 4e to afford intermediate oxonium ion 20 (Scheme 6)
followed byringopeningcan afford eitherof the two carbocations 21
or 22. Minimization of initially formed oxonium ion 20 results in
a product where there is significant bond lengthening of the C4aeO
d
d
*
ꢀ
ꢀ
d
bond (2.91 A) versus the C9eO bond (1.43 A). In the neutral benzo-
proximity of this hydrogen to oxygen of the bay region methoxy
group (2.1 A in the energy-minimized structure). In all of the
oxanorbornene these bonds are of nearly equal length
ꢀ
ꢀ
ꢀ
(C4aeO¼1.46 A; C9eO¼1.44 A). The minimized structure of 20 has
structural features similar to carbocation 21, and energy minimiza-
tion results in a product of only slightly higher energy relative to 20.
Carbocation 21 is heavily stabilized through resonance interaction
with the enol ether methoxy group. Opening of the oxonium in the
other direction to afford para-quinonemethide-like species 22 is
considerably less favorable. The energetics of benzo-oxanorbornene
ring opening are very similar for the cases where R¼H or R¼Me,
however greater stabilization of a tertiary carbocation reduces the
energy difference between 21 and 22.
After the ring-opening process, deprotonation can afford either
of conjugated dienes 23 or 24 (Scheme 7). The thermodynamically
more favorable compound is isomer 23. Although 23 is more favored
product of simple deprotonation, the isomerization/deconjugation
product 25 is even more stable, presumably due to steric interaction
of the TMS and aromatic groups in 23. This difference is even also
present in the dehydration products 17g and 18g. In the conjugated
isomer 17g, there is minimal overlap of the alkene group and the
naphthalene ring system; the C3eC4eC4aeC4b dihedral angle is 146ꢀ
in the energy minimum conformation. Compound 17g was not
observed, however in one experimental run the isomerization
product 18g was observed prior to chromatography. Conversion of
enol ether 17g to the alkene isomer 18g is unlikely to be a thermal
process, however the presence of chromium could serve as a double
bond isomerization catalyst.24 Based on the experimental observa-
tionand calculations, the mostreasonable pathwayforconversion of
oxanorbornenes to aromatic systems is depicted in Scheme 8, and
desilylated dihydrophenanthrenes (16), the eCH2CH2e group
appears as two triplets, each integrating for two hydrogens.
However this same group in compound 17b appears as four dis-
tinct ddd patterns. This is likely due to the nonconjugated ar-
rangement of the enol ether double bond due to steric interaction
between the methoxy and trimethylsilyl groups, which results in
a chiral compound.
A likely scenario for the conversion of benzo-oxanorbornene in-
termediate 4 to dihydrophenanthrene derivative 16 is depicted in
Scheme 5. Although no acid was deliberately added to the reaction
mixture, acid is a necessary component in all of the proposed mech-
anisms for the conversion of benzo-oxanorbornene intermediates to
the corresponding naphthalenes (see Scheme 6). In the absence of
acid, coordination of the benzo-oxanorbornene oxygen to a chro-
miumspecies22 couldserveasaLewisacidtoinitiatethering-opening
dehydration sequence. The presence of electron-donating groups
para to the benzylic alcohol group is expected to facilitate the de-
hydration step through highly stabilized carbocation intermediates.
In order to prevent the dehydration process and prevent formation of
carbocation and oxonium ion intermediates, the reaction in entry 7
was examined in the presence of the weakly basic additive collidine.
Surprisingly, the reaction in the presence of collidine simply resulted
in an enhanced yield of the dihydrophenanthrene derivative 16g and
noalterationof thereactionpathway. Theroleofcollidineisnottotally
clear, however it is likely related to its ability to serve as a ligand for
chromium.23

4958
A. Camacho-Davila et al. / Tetrahedron 66 (2010) 4954e4960
OMe
3. Conclusions
H
TMS
H
The coupling of
g,d-unsaturated carbene complexes with 2-
MeO
alkynylbenzaldehyde/acetophenone derivatives featuring electron-
rich oxygenated aromatic ring systems leads to dihydrophenan-
threnes in a net [5þ5]-cycloaddition involving sequential carbene
complexealkyne coupling, isobenzofuran formation, and intra-
molecular DielseAlder reaction. The net coupling process is an
intermolecular one, which is inherently superior to methods based
on intramolecular systems. The initially formed benzo-oxa-
norbornenes undergo net dehydration and desilylation processes,
which are enhanced by the presence of electron-donating groups.
Electron-withdrawing methanesulfonyloxy groups suppress the
dehydration pathway and result in hydroxyphenanthrenone
derivative.
H
OH
R
21
OMe
OMe
OH
TMS
TMS
+
MeO
MeO
H
24
OH
23
R
R
OMe
Relative Energy 23-25
R = H (R = Me)
23 - 0 (0)
24 - +4.9 (+5.3)
25 - -3.6 (-3.4)
TMS
MeO
4. Experimental25
(all values in kcal/mol)
25
OH
R
4.1. General procedure for carbene complexealkyne coupling
OMe
OMe
3
To a refluxing 0.1 M solution of the alkyne-aldehyde/ketone
(1 equiv) in dioxane (10 mL/mmol) was added over a 1 h period
a solution of carbene complex 2 (1.2 equiv) in dioxane (10 mL/
mmol). After the addition, the reflux was continued for 24 h and the
mixture was allowed to reach room temperature. The dioxane was
removed on a rotary evaporator and the residue was suspended in
hexane/ethyl acetate and filtered through Celite. The filtrate was
concentrated under reduced pressure and the residue purified by
flash chromatography on silica gel.
4
TMS
TMS
4b
ΔE =
-3.5 kcal/mol
4a
MeO
MeO
MeO
MeO
18g
17g
Scheme 7.
involves opening to the carbocation/oxonium ion species 21, fol-
lowed by deprotonation to afford the hydrated naphthalene de-
rivative 23. Water loss and energetically favorable deconjugation
affords the allylsilane/enol ether. The final product then results from
protiodesilylation to afford the observed dihydrophenanthrene
products.
4.2. Coupling of carbene complex 2 with aldehyde 1a (Table 1,
entry 1)
OMe
OMe
The general procedure was followed using carbene complex 2
(348 mg, 1.20 mmol) and aldehyde 1a (265 mg, 1.00 mmol). Final
purification was achieved by flash chromatography on silica gel
using 4:1 hexane/ethyl acetate as eluent. Dihydrophenanthrene
16a was isolated (158 mg, 58% yield). 1H NMR (200 MHz, CDCl3):
TMS
TMS
H+
MeO
MeO
H
H
O
H
O
d
7.53 (d, 1H, J¼8.7 Hz), 7.44 (d, 1H, J¼8.1 Hz), 7.24 (br s, 1H), 7.21 (d,
4e
20
1H, J¼8.7 Hz), 7.12 (d, 1H, J¼8.1 Hz), 3.98 (s, 3H), 3.82 (s, 3H), 3.81 (s,
3H), 2.99 (t, 2H, J¼6.7 Hz), 2.44 (t, 2H, J¼6.7 Hz); 13C NMR
OMe
H
OMe
(100 MHz, CDCl3):
d 159.6, 149.8, 144.9, 130.2, 129.5, 125.5, 125.1,
TMS
TMS
124.8, 124.6, 124.5, 113.6, 96.3, 61.0, 56.8, 54.6, 30.1, 26.5; MS (EI):
270 (Mþ, 100), 255 (52), 240 (12), 224 (16), 212 (33); HRMS (EI):
calcd for C17H18O3 270.1256, found 270.1265.
-H2O
MeO
MeO
OH
OH
21
23
4.3. Coupling of carbene complex 2 with aldehyde 1b (Table 1,
entry 2)
OMe
OMe
TMS
TMS
H+
The general procedure was followed using carbene complex 2
(346 mg, 1.20 mmol) and aldehyde 1b (248 mg, 1.00 mmol). Final
purification was achieved by flash chromatography on silica gel
using 4:1 hexane/ethyl acetate as eluent. Dihydrophenanthrene
17b was isolated (214 mg, 65% yield). 1H NMR (400 MHz, CDCl3):
Silica
MeO
MeO
17e
18e
d
7.50 (d, 2H, J¼8.0 Hz), 7.18 (d, 1H, J¼8.0 Hz), 7.14 (d, 2H, J¼8.0 Hz),
OMe
5.98 (s, 1H), 3.73 (s, 3H), 3.57 (s, 3H), 2.85 (ddd, 1H, J¼15.0, 14.7,
6.3 Hz), 2.74 (ddd, 1H, J¼15.0, 6.3, 2.0 Hz), 2.53 (ddd, 1H, J¼15.0, 5.3,
2.0 Hz), 2.21 (ddd, 1H, J¼15.0, 14.7, 5.3 Hz), 0.02 (s, 9H); 13C NMR
MeO
(CDCl3):
d 165.8, 145.4, 140.5, 134.4, 131.6, 129.8, 125.2, 125.1, 123.4,
16e
Scheme 8.
116.9, 115.5, 60.6, 55.8, 30.6, 22.9, 1.2; HRMS (ESI): calcd for
C18H25O3Si (MþH) 329.1573, found 329.1573.

A. Camacho-Davila et al. / Tetrahedron 66 (2010) 4954e4960
4959
4.4. Coupling of carbene complex 2 with aldehyde 1c (Table 1,
entry 3)
4.8. Coupling of carbene complex 2 with ketone 1g
The general procedure was followed using carbene complex 2
(300 mg, 1.03 mmol) and ketone 1g (280 mg, 1.00 mmol). Final
purification was achieved by flash chromatography on silica gel
using 4:1 followed by 3:2 hexane/ethyl acetate as eluent. Com-
pound 16g was isolated (115 mg, 40%). 1H NMR (200 MHz, CDCl3):
The general procedure was followed using carbene complex 2
(348 mg, 1.20 mmol) and aldehyde 1c (277 mg, 1.00 mmol). Final
purification was achieved by flash chromatography on silica gel
using 4:1 then 2:1 hexane/ethyl acetate as eluent. Compound 16c
was isolated (188 mg, 63%). 1H NMR (400 MHz, CDCl3):
d
7.54 (d,1H,
d 7.30 (s, 1H), 7.18 (s, 1H), 7.03 (s, 1H), 6.11 (s, 1H), 4.06 (s, 3H), 4.03
J¼8.8 Hz), 7.49 (d, 1H, J¼8.2 Hz), 7.23 (d, 1H, J¼8.2 Hz), 7.11 (d, 1H,
J¼8.8 Hz), 7.09 (br s, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.00 (t, 2H,
J¼7.6 Hz), 2.44 (t, 2H, J¼7.6 Hz), 2.40 (s, 3H); 13C NMR (100 MHz,
(s, 3H), 3.86 (s, 3H), 2.98 (t, 2H, J¼8.8 Hz), 2.60 (s, 3H), 2.48 (t, 2H,
J¼8.8 Hz); 13C NMR (50 MHz, CDCl3):
d 160.5, 148.9, 148.5, 128.8,
127.6, 127.4, 127.2, 126.0, 124.8, 103.7, 102.5, 91.8, 55.9, 55.7, 54.8,
29.5, 27.7, 19.6; MS (EI): 284 (M,100), 269 (54), 241 (30); HRMS (EI):
calcd for C18H20O3 284.1412, found 284.1407. If one omits the
chromatography step a different product consistent with 18g was
obtained in greater than 90% purity: 1H NMR (200 MHz, CDCl3):
CDCl3):
d 169.3, 160.3, 148.2, 141.2, 133.7, 130.8, 130.6, 126.5, 125.4,
124.3, 124.2, 120.6, 96.0, 61.6, 54.7, 30.0, 26.5, 20.8; IR (neat):
1764 cmꢁ1; HRMS (ESI): calcd for C18H19O4 (MþH) 299.1278, found
299.1288.
d
7.21 (s, 1H), 7.19 (s, 1H), 7.03 (s, 3H), 4.79 (br d, 1H, J¼4.0 Hz), 4.03
(s, 6H), 3.65 (s, 3H), 3.65e3.30 (m, 3H), 2.89 (s, 3H), 0.03 (s, 9H).
4.5. Coupling of carbene complex 2 with aldehyde 1d (Table 1,
entry 4)
4.9. Coupling of carbene complex 2 with ketone 1g in 10:1
dioxane/collidine
The general procedure was followed using carbene complex 2
(290 mg, 1.00 mmol) and aldehyde 1d (326 mg, 1.00 mmol) in 19:1
dioxane/water (10 mL). Final purification was achieved by flash
chromatography on silica gel using 4:1 followed by 1:1 hexane/
ethyl acetate as eluent. Compound 5d was isolated (300 mg, 72%).
A modification of the general procedure was followed using
carbene complex 2 (430 mg, 1.50 mmol) and ketone 1g (280 mg,
1.00 mmol) in collidine (1 mL) and dioxane (10 mL) at 80 ꢀC. After
a 24 h period at 80 ꢀC, the mixture was cooled to room temperature
and filtered through a thin layer of Celite and the solvent was re-
moved on a rotary evaporator. The residue was dissolved in
dichloromethane and washed with saturated aqueous ammonium
chloride solution and then dried over sodium sulfate. The solution
was concentrated under reduced pressure and then purified by
flash chromatography on silica gel using 14:1 hexane/ethyl acetate
as an eluent to afford compound 16g (260 mg, 92%).
1H NMR (400 MHz, CDCl3):
d
7.30 (d, 1H, J¼8.1 Hz), 7.08 (d, 1H,
J¼8.1 Hz), 4.93 (t, 1H, J¼6.6 Hz), 3.63 (s, 3H), 3.30 (s, 3H), 2.60e2.50
(m, 2H), 2.34 (ddd, 1H, 17.0, 13.8, 4.3 Hz), 2.26 (ddd, 1H, J¼12.9, 8.8,
4.3 Hz), 2.17 (ddd, 1H, J¼13.8, 9.6, 3.8 Hz), 2.02e1.90 (m, 2H), 1.85
(br s, 1H), 0.06 (s, 9H); 13C NMR (100 MHz, CDCl3):
d 203.2, 160.3,
149.7, 142.4, 142.0, 141.4, 132.4, 125.0, 122.6, 69.0, 60.7, 39.2, 37.8,
37.6, 36.4, 31.4, 0.0; IR (neat): 3409, 1645 cmꢁ1; Mass Spec (FAB):
433 (MþNa, 16), 411 (MþH, 16), 395 (100); HRMS: calcd for
C19H27O6SSi (MþH) 411.1298, found 411.1282.
Acknowledgements
This work was supported by the SCORE program of NIH
(SC1GM083693).
4.6. Coupling of carbene complex 2 with aldehyde 1e (Table 1,
entry 5)
Supplementary data
The general procedure was followed using carbene complex 2
(221 mg, 0.76 mmol) and aldehyde 1e (161 mg, 0.69 mmol). Final
purification was achieved by flash chromatography on silica gel
using 4:1 hexane/ethyl acetate as eluent. Compound 16e was iso-
Detailed experimental procedures for syntheses of alkyne-car-
bonyl compounds from commercially available materials, copies of
1H NMR and 13C NMR data for products in Table 1, and computa-
tional details and SCF energies for structures depicted in Schemes 6
and 7. Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2010.04.117. These data
include MOL files and InchIkeys of the most important compounds
described in this article.
lated (95 mg, 57%). 1H NMR (200 MHz, CDCl3):
d 7.72 (d, 1H,
J¼8.8 Hz), 7.50 (d, 1H, J¼8.2 Hz), 7.32 (d, 1H, J¼2.2 Hz), 7.16 (d, 1H,
J¼8.2 Hz), 7.13 (dd, 1H, J¼8.8, 2.4 Hz), 6.17 (s, 1H), 3.98 (s, 3H), 3.88
(s, 3H), 3.05 (t, 2H, J¼8.2 Hz), 2.52 (t, 2H, J¼8.2 Hz); 13C NMR
(50 MHz, CDCl3):
d 161.0, 157.46, 130.1, 130.0, 129.4, 129.2, 128.5,
124.1, 116.7, 101.8, 91.6, 55.3, 54.8, 29.6, 29.5, 27.5; IR (neat): 1657
(s), 1621 (s) cmꢁ1; Mass Spec (EI): 240 (M, 100), 225 (45); HRMS
(EI): calcd for C16H16O2 240.1150, found 240.1148.
References and notes
1. For a recent review of syntheses, see: Harvey, R. G. Curr. Org. Chem. 2004, 8,
303e323.
2. Recent reports include: (a) Liu, F.; Xie, L. H.; Tang, C.; Liang, J.; Chen, Q. Q.; Peng,
B.; Wei, W.; Cao, Y.; Huang, W. Org. Lett. 2009, 11, 3850e3853; (b) Zhao, C.;
Chen, X.; Gao, C.; Ng, M. K.; Ding, H.; Park, K.; Gao, Y. Synth. Met. 2009, 159,
995e1001; (c) Natsume, Y.; Minakata, T.; Aoyagi, T. Thin Solid Films 2009, 517,
4.7. Coupling of carbene complex 2 with aldehyde 1f
The general procedure was followed using carbene complex 2
(450 mg, 1.55 mmol) and aldehyde 1f (375 mg, 1.29 mmol). Final
purification was achieved by flash chromatography on silica gel
using 4:1 hexane/ethyl acetate as eluent. Compound 16f was iso-
3005e3010; (d) Cinacchi, G.; Prampolini, G. J. Phys. Chem.
C 2008, 112,
9501e9509; (e) Wang, X.; Zhi, L.; Tsao, N.; Tomovic, Z.; Li, J.; Mullen, K. Angew.
Chem., Int. Ed. 2008, 47, 2990e2992; (f) Rosales, L.; Pacheco, M.; Barticevic, Z.;
Latge, A.; Orellana, P. A. Nanotechnology 2008, 19, 065402/1e065402/5; (g) Wu,
J. Curr. Org. Chem. 2007, 11, 1220e1240.
3. (a) Huang, X.; He, J.; Niu, X.; Menzel, K. D.; Dahse, H. M.; Grabley, S.; Fiedler, H.
P.; Sattler, I.; Hertweck, C. Angew. Chem., Int. Ed. 2008, 47, 3995e3998; (b) Kock,
I.; Maskey, R. P.; Biabani, M. A. F.; Helmke, E.; Laatsch, H. J. Antibiot. 2005, 58,
530e534.
4. (a) Chen, Y.; Luo, J.; Zhu, X. X. J. Phys. Chem. B 2008, 112, 3402e3409; (b) Frade,
V. H. F.; Barros, S. A.; Moura, J. C. V. P.; Coutinho, P. J. G.; Goncalves, M. S. T.
Tetrahedron 2007, 63, 12405e12418; (c) Ishikawa, K.; Sato, S.; Ohuchi, S. Pept.
Sci. 2003, 39, 423e424.
lated (242 mg, 60%). 1H NMR (200 MHz, CDCl3):
d 7.38 (d, 1H,
J¼8.1 Hz), 7.24 (s, 1H), 7.12 (s, 1H, J¼8.1 Hz), 7.07 (s, 1H), 6.10 (s, 1H),
4.03 (s, 3H), 3.98 (s, 3H), 3.81 (s, 3H), 3.00 (t, 2H, J¼8.8 Hz), 2.47 (t,
2H, J¼8.8 Hz); 13C NMR (50 MHz, CDCl3):
d 161.2, 149.3,148.8,129.2,
128.8, 127.4, 124.7, 122.9, 107.2, 101.9, 91.8, 55.9, 55.8, 54.9, 29.6,
27.7; MS (EI): 270 (M, 100), 255 (38), 227 (27); HRMS (EI): calcd for
C17H18O3 270.1256, found 270.1251.

4960
A. Camacho-Davila et al. / Tetrahedron 66 (2010) 4954e4960
5. Hecht, S. S. Biotechnol.: Pharm. Aspects 2008, 9, 463e494.
6. For a recent review, see: Chemler, S. R. Curr. Bioact. Cmpd. 2009, 5, 2e19.
7. For a recent review, see: Ríos, J. L.; Máñez, S.; Giner, R. M.; Recio, M. C. In The
Alkaloids; Cordell, G. A, Ed.; Academic San Diego: 2000, pp 57e117.
8. For the latest in a continuing annual review series, see: Hanson, J. R. Nat. Prod.
Rep. 2007, 24, 1332e1341.
18. Camacho-Davila, A.; Herndon, J. W. J. Org. Chem. 2006, 71, 6682e6685.
19. Nimgirawath, S.; Udomputtimekakul, P.; Taechowisan, T.; Wanbanjob, A.; Shen,
Y. Chem. Pharm. Bull. 2009, 57, 368e376.
20. For linear free energy parameters of methanesulfonyloxy groups, see: Stang, P.
J.; Anderson, A. G. J. Org. Chem. 1976, 41, 781e785.
21. (a) Pascual, C.; Meier, J.; Simon, W. Helv. Chim. Acta 1969, 48, 164e168; (b)
Friebolin, H. Basic One- and Two-Dimensional NMR Spectroscopy, 4th ed.; Wiley-
VCH: Weinheim, 2005, pp 142e143.
9. For a recent review of phenanthrene natural products, see: Kovács, A.; Vasas,
A.; Hohmann, J. Phytochemistry 2008, 69, 1084e1100.
10. Koo, S.; Liebeskind, L. S. J. Am. Chem. Soc. 1995, 117, 3389e3404.
11. (a) Dotz, K. H.; Dietz, R. Chem. Ber. 1978, 111, 2517e2526; (b) Bao, J.; Wulff, W. D.;
22. Choi, M. G.; White, D.; Brown, T. L. Inorg. Chem. 1994, 33, 5591e5594.
23. Notable examples where ligands alter the reaction pathway for carbene com-
plexealkyne couplings include: (a) Flynn, B. L.; Schirmer, H.; Deutsch, M.; de
Meijere, A. J. Org. Chem. 2001, 66, 1747e1754; (b) Bos, M. E.; Wulff, W. D.; Miller,
R. A.; Chamberlin, S.; Brandvold, T. A. J. Am. Chem. Soc. 1991, 113, 9293e9319; (c)
Xu, Y. C.; Wulff, W. D. J. Org. Chem. 1987, 52, 3263e3275; (d) Herndon, J. W.;
Zora, M.; Patel, P. P.; Chatterjee, G.; Matasi, J. J.; Tumer, S. U. Tetrahedron 1993,
49, 5507e5530.
24. Examples of alkene isomerization during reactions involving chromium(0)
carbonyl complexes include: (a) Ghorai, B. K.; Herndon, J. W. Organometallics
2003, 22, 3951e3957; (b) Alvarez, C.; Parlier, A.; Rudler, H.; Yefsah, R.; Daran, J.
C.; Knobler, C. Organometallics 1989, 8, 2253e2259; (c) Alvarez-Toledano, C.;
Parlier, A.; Rudler, H.; Rudler, M.; Daran, J. C.; Knobler, C.; Jeannin, Y. J. Orga-
nomet. Chem. 1984, 328, 357e373; (d) Tsonis, C. P.; Hwang, J. S. J. Mol. Catal.
1984, 26, 219e229; (e) Heaton, B. T.; McCaffrey, D. J. A. J. Chem. Soc., Dalton
Trans. 1979, 1078e1083; (f) Wrighton, M.; Hammond, G. S.; Gray, H. B. J. Or-
ganomet. Chem. 1974, 70, 283e301.
€
Dominy, J. B.; Fumo, M. J.; Grant, E. B.; Rob, A. C.; Whitcomb, M. C.; Yeung, S. M.;
Ostrander, R. L.; Rheingold, A. L. J. Am. Chem. Soc. 1996, 118, 3392e3405; (c)
€
Dotz, K. H.; Stendl, J.; Nieger, M. Z. Anorg. Allg. Chem. 2009, 635, 221e237.
12. Danheiser, R. L.; Casebier, D. S.; Fabriooza, F. J. Org. Chem. 1995, 60, 8341e8350.
13. (a) Wang, K.; Lu, M.; Yu, A.; Zhu, X.; Wang, Q. J. Org. Chem. 2009, 74, 935e938; (b)
Lupatelli, P.; D’Auria, M.; Di Blasio, N.; Lenti, F. Eur. J. Org. Chem. 2009, 141e145.
14. Bonifacio, M. C.; Robertson, C. R.; Jung, J. Y.; King, B. T. J. Org. Chem. 2005, 70,
8522e8526.
15. (a) Menon, S.; Sinha-Mahapatra, D. K.; Herndon, J. W. Tetrahedron 2007, 63,
8788e8793; (b) Li, R.; Zhang, L.; Camacho-Davila, A.; Herndon, J. W. Tetrahe-
dron Lett. 2005, 46, 5117e5120; (c) Ghorai, B. K.; Menon, S.; Johnson, D. L.;
Herndon, J. W. Org. Lett. 2002, 4, 2121e2124; (d) Ghorai, B. K.; Herndon, J. W.;
Lam, Y. F. Org. Lett. 2001, 3, 3535e3538.
16. For a review, see: Friedrichsen, W. Adv. Heterocycl. Chem. 1999, 73, 1e96.
17. (a) Meegalla,S. K.;Rodrigo,R.J. Org. Chem.1991,56,1882e1888;(b)Duan,S.;Cress,K.;
Waynant, K.; Ramos-Miranda, E.; Herndon, J. W. Tetrahedron 2007, 63, 2959e2965.
25. For a general experimental, see Supplementary data.