Synthesis of hydrophenanthrenes through a 'green' Fischer carbene-alkyne coupling process

Article abstract of DOI:10.1016/j.tetlet.2005.05.126

Coupling of alkynylbenzoyl systems with γ,δ-unsaturated Fischer carbene complexes leads to the formation of hydrophenanthrene derivatives. This reaction is not affected by aqueous systems, which offer a further advantage such that chromium hexacarbonyl sublimes during the reaction process. Chromium carbene-alkyne coupling processes can thus be performed in environmentally friendly solvents with substoichiometric net consumption of chromium hexacarbonyl.

Full text of DOI:10.1016/j.tetlet.2005.05.126

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5117–5120
Synthesis of hydrophenanthrenes through a ‘green’ Fischer
carbene–alkyne coupling process
Rongti Li, Lei Zhang, Alejandro Camacho-Davila and James W. Herndon*
Department of Chemistry and Biochemistry, New Mexico State University, MSC 3C, Las Cruces, NM 88003, USA
Received 11 May 2005; accepted 31 May 2005
Available online 15 June 2005
Abstract—Coupling of alkynylbenzoyl systems with c,d-unsaturated Fischer carbene complexes leads to the formation of hydro-
phenanthrene derivatives. This reaction is not affected by aqueous systems, which offer a further advantage such that chromium
hexacarbonyl sublimes during the reaction process. Chromium carbene–alkyne coupling processes can thus be performed in envi-
ronmentally friendly solvents with substoichiometric net consumption of chromium hexacarbonyl.
Ó 2005 Elsevier Ltd. All rights reserved.
A novel two-component stitching of the hydrophen-
anthrene ring system via the reaction of alkynylbenz-
aldehyde derivatives with c,d-unsaturated carbene com-
plexes has recently been developed in this laboratory
(e.g., conversion of 1a+2b to 5b in Scheme 1).1 The reac-
tion proceeds with a high degree of diastereo-selectivity
when chiral c,d-unsaturated carbene complexes (e.g., 2b)
were employed to afford a single compound (e.g., 5b) in
good yield. The analogous reaction using simple bute-
nylcarbene complex 2a is considerably less efficient than
the more highly substituted examples presented in Refs.
1a–c,2 and afforded a low yield of a mixture of com-
plexed and uncomplexed derivatives after silica gel chro-
matography. As part of a general effort to prepare
hydrophenanthrene natural products (including mor-
phine alkaloids and abietanes) using the reaction in
Scheme 1, the coupling of highly oxygenated alkynyl-
benzoyl derivatives (e.g., 1c, Scheme 2) with simple
c,d-unsaturated carbene complexes was tested. The most
satisfactory yield optimization experiment involved the
deliberate addition of water to the reaction mixture.3
Scheme 1.
When the coupling of alkynylbenzaldehyde 1c and car-
bene complex 2a was conducted in 19:1 dioxane–water,
Since carbene complex 2a was originally prepared from
the yield of hydrophenanthrene 5c was higher than in
chromium hexacarbonyl (see Scheme 3), the net effect is
any other experiment and chromium hexacarbonyl was
that the overall transformation is substoichiometric in
deposited onto the condenser.
chromium. In this letter, these two effects will be ex-
plored in more depth. The ultimate goal is to devise a
system where chromium carbene complexes couple with
an alkyne in a process that employs cheap and environ-
Keywords: Carbene complexes; Alkynes; Isobenzofurans; Diels–Alder
reaction; Aqueous reactions.
mentally friendly solvents with minimal net
consumption of chromium.4 Although alkylation of
chromium carbene complex stabilized anions,5 synthesis
*
Corresponding author. Tel.: +1 505 6462487; fax: +1 505 6462649;
e-mail: jherndon@nmsu.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.126

5118
R. Li et al. / Tetrahedron Letters 46 (2005) 5117–5120
of carbene complexes,6 and pKa measurements7 can be
conducted in water at or below room temperature, stud-
ies of aqueous thermally induced chromium carbene–
alkyne couplings are extremely limited.8
Prior to evaluation of the aqueous phenanthrene synthe-
sis, the reaction of complex 2a with various 2-alkynyl-
benzoyl systems in conventional ethereal solvents was
tested (Table 1). As noted in Table 1, the reaction affor-
ded a diverse array of different products related to oxa-
norbornene derivative 4, and to some extent the distri-
bution of these products could be controlled through
the work-up procedure. These substrates will be the
focus of aqueous-phase investigations in anticipation
that a viable high-yielding and convenient procedure
can be developed for the isolation of the desired products
5. For the convenience of evaluating the overall efficiency
Scheme 2.
Scheme 3.
Table 1. Reaction of butenylcarbene complexes 2a/2c with alkynylbenzoyl systems
Entry
R1
H
R2
H
R3
Conditionsa
SiO2
Products
1 (1a+2a)
Me
5a (5%)
6a (20%)
10a (20%)
10d (56%)
5e (15%)
6e (trace)
9e (4%)b
10e (51%)b
11e (3%)b
5f (9%)
2 (1a+2a)
3 (1d+2a)
4 (1e+2a)
H
H
H
H
Me
Me
Me
HCl
HCl
SiO2
n-Bu
TMS
5 (1e+2a)
H
TMS
Me
HCl
6 (1f+2c)
7 (1f+2c)
Ph
Ph
n-Bu
n-Bu
Bn
Bn
SiO2
HCl
8f (67%)
8f (11%)
10f (61%)
a SiO2—the product after extractive work-up was purified by Flash chromatography; HCl—After the reaction mixture cooled to room temperature,
1 M aqueous HCl was added.
b R2 = H in the products 9–11.

R. Li et al. / Tetrahedron Letters 46 (2005) 5117–5120
5119
of the process, in some cases the crude reaction mixture
was treated with aqueous HCl, which afforded predomi-
nantly dehydration products. The results in Table 1
reveal that: (1) the yield of adducts are generally higher
using phenyl ketones instead of aldehydes (compare
entries 6 and 7 with all others),9 (2) the yields of adducts
with internal alkynes are generally higher than those with
terminal alkynes (note the unusually low yields in entries
1 and 2), and (3) the yields of the desired adducts 5 are
highest when the crude reaction is subjected to chroma-
tography on silica gel, however even under these optimal
conditions there are often significant amounts of dehy-
dration/oxidation byproducts (entry 6) and chromium
is not efficiently decomplexed from the arene (entries 1
and 4). The reaction is of similar efficiency with both
methoxycarbene complexes and benzyloxycarbenes
(entries 6 and 7), despite the known thermal chemistry
of benzyloxycarbene complexes.10
ate-excellent yield by merely scraping the condenser
after the reaction is over. The yield of hydrophenanth-
rene 5e was not affected by the amount of water or eth-
anol in the reaction mixture. The reaction could even be
performed successfully in pure water if surfactants were
added to the reaction mixture (entries 7–9) and was
equally successful using pure sodium dodecyl sulfate
(SDS) and hand soap. The major complication in the
experiments using anionic surfactants (entries 7 and 9)
is that the extractive work-up that is typically employed
is difficult in the presence of the surfactant and required
the use of dichloromethane instead of ether.11 These
conditions were also effective for reactions using the
butylacetylene analog (entries 10 and 11) and the phenyl
ketone analog (entries 15 and 16), in all cases leading
exclusively to the desired adduct 5.
These reaction conditions were not effective in promot-
ing the coupling of the terminal alkyne (entries 12–14).
The reaction in entry 12 of Table 2 afforded only the di-
enol ether 14 (Scheme 4). The reaction in entry 13 led
to the alkylidenephthalan 13. Formation of this product
suggests that either: (1) the rate of the Diels–Alder step
of the tandem reaction process is lower in this system,
(2) that the presence of water has an activating effect
on a 1,7-hydrogen shift process,12 or (3) that the iso-
benzofuran intermediate 3a can directly hydrolyze to
afford the alkylidenephthalan.
Next, the reaction of carbene complex 2a with alkynyl-
benzoyl systems was tested in the presence of water
and various water-like solvent systems (Table 2). As
noted in entries 1–9 of Table 2, the reaction of the silyl-
ated alkyne was highly tolerant of an aqueous environ-
ment. Furthermore, the reaction was free of dehydration
products and arene–chromium complexes, and only the
desired product 5e was obtained. Chromium hexacar-
bonyl can be recovered from the system in a moder-
Table 2. Reaction of c,d-unsaturated carbene complex 2a with alkynylbenzaldehydes
R1
R2
Solventa
5 (%)
b
Cr(CO)6 (%)
Entry
1
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
n-Bu
n-Bu
H
95:5 d:w
90:10 d:w
75
89
90
89
89
59
81
70
80
63
77
60
67
71
85
35
61
71
74
74
74
76
76
84d
74
56
58
0f
2
3
80:20 d:w
70:30 d:w
50:50 d:w
4
5
6
95:5 e:w
7
w+10% SDSc
w+5% Bu4NBr
w+hand soape
95:5 d:w
8
9
10
11
12
13
14
15
16
w+5% Bu4NBr
95:5 d:w
70:30 d:w
H
0f
H
w+5% Bu4NBr
w+10% SDS
w+5% Bu4NBr
0
n-Bu
n-Bu
80
75
a d = dioxane, w = water, e = ethanol.
b The theoretical yield of Cr(CO)6 is 0.83 mol/mol of carbene complex used.
c SDS = sodium dodecylsulfate.
d For an experimental procedure, see Ref. 13.
e The major ingredients listed are water, sodium dodecylbenzenesulfonate, and SDS.
f See Scheme 4.

5120
R. Li et al. / Tetrahedron Letters 46 (2005) 5117–5120
4. (a) Other procedural improvements for chromium car-
bene–alkyne couplings have been reported. For the use of
microwave irradiation, see: (a) Hutchinson, E. J.; Kerr,
W. J.; Magennis, E. J. Chem. Commun. 2002, 2262–2263;
For solution phase sonication, see: (b) Pulley, S. R.;
Subhabrata, S.; Vorogushin, A.; Swanson, E. Org. Lett.
1999, 1, 1721–1723; For sonication and dry-state absorp-
tion, see: (c) Harrity, J. P. A.; Kerr, W. J.; Middlemiss, D.
Tetrahedron 1993, 49, 5565–5576; For dry state absorp-
tion, see: (d) Harrity, J. P. A.; Kerr, W. J.; Middlemiss, D.
Tetrahedron Lett. 1993, 34, 2995–2998.
5. (a) Amin, S. R.; Sarkar, A. Organometallics 1995, 14, 547–
550; (b) Hoye, T. R.; Vyvyan, J. R. J. Org. Chem. 1995,
60, 4184–4195.
6. (a) Hoye, T. R.; Chen, K.; Vyvyan, J. R. Organometallics
1993, 12, 2806–2809; (b) Zheng, Q. H.; Su, J. Synth.
Commun. 2000, 30, 177–185; (c) Bao, J.; Wulff, W. D.;
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, 3392–4405.
7. See: Bernasconi, C. F.; Ruddat, V.; Wenzel, P. J.; Fischer,
H. J. Org. Chem. 2004, 69, 5232–5239, and references cited
therein.
8. Herndon, J. W. Curr. Org. Chem. 2003, 7, 329–352.
9. This can likely be attributed to the enhanced stability of
the phenyl-substituted isobenzofuran intermediate. Fried-
richsen, W. Adv. Heterocycl. Chem. 1999, 73, 1–96.
10. Nandi, M.; Sathe, K. M.; Sarkar, A. Chem. Commun.
1992, 793–794.
Scheme 4.
In summary, we have shown that carbene–alkyne cou-
pling can be performed in an aqueous solvent system.
About 60–90% of the chromium can be recovered. Un-
like most systems that are not catalytic but allow metal
recovery, this one is practical. The metal comes out of
the reaction in the same form in which it was purchased
commercially, and the recovery process amounts to a
simple scraping of the condenser.
11. We acknowledge that the reaction will not be truly
environmentally friendly until this aspect of the procedure
is addressed.
12. Jiang, D.; Herndon, J. W. Org. Lett. 2000, 2, 1267–
1269.
13. A mixture of alkyne–aldehyde 1e (101 mg, 0.50 mmol) and
carbene complex 2a (189 mg, 0.65 mmol) in water (30 mL)
and tetrabutylammonium bromide (8.1 mg, 5 mol %) was
heated to reflux under nitrogen for a 24 h period. Scraping
the condenser yielded chromium hexacarbonyl (83 mg,
70%). The mixture was cooled to room temperature and
extracted three times with dichloromethane. The product
was purified by flash chromatography on silica gel using
1:1 hexane–ethyl acetate as the eluent to afford compound
5e (120 mg, 84% yield). 1H NMR (CDCl3): d 7.46 (d,
1H, J = 7.6 Hz), 7.43 (td, 1H, J = 7.6, 1.6 Hz), 7.33 (d, 1H,
J = 7.6 Hz), 7.30 (td, 1H, J = 7.6 Hz), 4.98 (q, 1H,
J = 5.2 Hz), 2.62 (dddd, 1H, J = 11.2, 7.0, 7.0, 5.2 Hz),
2.47 (ddd, 1H, J = 17.2, 3.8, 3.0 Hz), 2.33 (ddd, 1H,
J = 13.6, 6.8, 4.8 Hz), 2.30 (ddd, 1H, J = 16.8, 4.8, 2.4 Hz),
2.14 (m, 1H) 2.12 (br d, 1H, J = 5.4 Hz), 1.80 (m, 2H), 0.02
(s, 9H); D20: d 4.98 (t, 1H, J = 5.44 Hz), peak at d 2.12
disappears; 13C NMR (CDCl3): d 203.7, 169.5, 141.5,
137.7, 136.6, 131.0, 130.6, 127.5, 127.2, 69.3, 40.2, 37.9,
37.5, 29.9, 1.7; IR (neat): 1633 cmÀ1; MS (EI): 286 (M+,
15), 271 (100), 268 (98), 251 (21); HRMS: calcd for
C17H22O2Si 286.1389, found 286.1391.
Acknowledgements
This research was supported by the SCORE program of
NIH.
References and notes
1. (a) Ghorai, B. K.; Herndon, J. W.; Lam, Y. F. Org. Lett.
2001, 3, 3535–3538; (b) Ghorai, B. K.; Menon, S.;
Johnson, D. L.; Herndon, J. W. Org. Lett. 2002, 4,
2121–2124; (c) Ghorai, B. K.; Herndon, J. W. Organo-
metallics 2003, 22, 3951–3957.
2. The different reaction efficiencies can likely be attributed
to the gem dialkyl effect. Jung, M. E.; Gervay, J. J. Am.
Chem. Soc. 1991, 113, 224–232.
3. For the effect of adding water on chromium carbene–
alkyne couplings, see: Herndon, J. W.; Patel, P. P.
Tetrahedron Lett. 1997, 38, 59–62.