Intramolecular Nicholas reactions in the synthesis of dibenzocycloheptanes. Synthesis of allocolchicine NSC 51046 and analogues and the formal synthesis of (-)-allocolchicine

Article abstract of DOI:10.1021/jo101953n

The preparation of dibenzocycloheptyne-Co₂(CO)₆ complexes by intramolecular Nicholas reactions of biaryl-2-propargyl alcohol-Co₂(CO)₆ derivatives is described. Reductive decomplexation of the dibenzocycloheptyne

Full text of DOI:10.1021/jo101953n

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Intramolecular Nicholas Reactions in the Synthesis of
Dibenzocycloheptanes. Synthesis of Allocolchicine NSC 51046 and
Analogues and the Formal Synthesis of (-)-Allocolchicine
Sinisa Djurdjevic,†,‡ Fei Yang,† and James R. Green*,†
†Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON N9B 3P4, Canada, and
‡St. Clair College of Applied Arts and Technology, Windsor, ON N9A 6S4, Canada
jgreen@uwindsor.ca
Received October 3, 2010
The preparation of dibenzocycloheptyne-Co2(CO)6 complexes by intramolecular Nicholas reactions
of biaryl-2-propargyl alcohol-Co2(CO)6 derivatives is described. Reductive decomplexation of the
dibenzocycloheptyne-Co2(CO)6 complexes affords the corresponding dibenzocycloheptenes, indivi-
dual members of which have been employed in a formal total synthesis of (-)-allocolchicine, the
preparation of 6,7-dihydro-3,4,9,10,11-pentamethoxy-5H-dibenzo[a,c]cyclohepten-5-one, and the
enantioselective total syntheses of NSC 51046 and its 3,8,9,10-tetramethoxy regioisomer.
Introduction
of additional naturally occurring allocolchicines, including
(-)-androbiphenyline (4), (-)-colchibiphenyline (5), (-)-
jerusalemine (6), (-)-salimine (7), and (-)-suhailamine, have
also been isolated;2 the latter two of these have undergone
structural revision or are structurally in question (Figure 1).3
Synthetic access to the allocolchicines historically has been
based on oxidation of colchicine itself,4 although racemic
syntheses or those involving resolution are known.3,5 More
recently, the activity of these compounds has stimulated an
interest in the enantioselective synthesis of allocolchicines.
Initiated by Wulff’s Diels-Alder based synthesis of (-)-
allocolchicine itself,6 members of this class of compounds
The allocolchicines are a group of compounds containing
a tricyclic 6,7,6-system with a highly oxygen-substituted A
ring. Individual members of this group, including (-)-allo-
colchcine (1), N-acetylcolchicinol methyl ether (NSC 51046, 2),
N-acetylcolchicinol (3), and its dihydrogenphosphate (ZD
6126, 4) have gained considerable attention by virtue of
having been found to be active against a number of cancer
cell lines.1 These act by inhibiting tubulin assembly and
polymerization, therefore arresting cell mitosis. A number
ꢀ
(1) (a) Perez-Ramırez, B.; Gorbunoff, M. J.; Timasheff, S. N. Biochem-
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istry 1998, 37, 1646–1661. (b) Guan, J.; Zhu, X.; Brossi, A.; Tachibana, Y.;
Bastow, K. F.; Verdier-Pinard, P.; Hamel, E.; McPhail, A. T.; Lee, K.
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Collect. Czech. Chem. Commun. 1999, 64, 217–228. (c) Buttner, F.;
Bergemann, S.; Guenard, D.; Gust, R.; Seitz, G.; Thoret, S. Bioorg. Med.
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2005, 65, 541–550.
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Haenel, F.; Seitz, G. Liebigs Ann./Receuil 1997, 2275–2279. (c) Diler, U.;
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(5) (a) Cook, J. W.; Jack, J.; Loudon, J. D.; Buchanan, G. L.; Macmillan,
J. J. Chem. Soc. 1951, 1397–1403. (b) Sawyer, J. S.; Macdonald, T. L.
(2) (a) Tojo, E.; Abu Zarga, M. H.; Freyer, A. J.; Shamma, M. J. Nat.
Prod. 1989, 52, 1163–1166. (b) Al-Tel, T. H.; Abu Zarga, M. H.; Sabri, S. S.;
Freyer, A. J.; Shamma, M. J. Nat. Prod. 1990, 53, 623–629. (c) Abu Zarga,
M. H.; Sabri, S.; Al-Tel, T. H.; Atta-ur-Rahman; Shah, Z.; Feroz, M. J. Nat.
Prod. 1991, 54, 936–940. (d) See also: Yusupov, M. K.; Sadykov, A. S. J. Gen.
Chem. USSR (Engl. Transl.) 1964, 34, 1686-1688; Zh. Obshch. Khim. 1964,
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Tetrahedron Lett. 1988, 29, 4839–4842. (c) Boye, O.; Brossi, A.; Yeh, H. J. C.;
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34, 1677-1680. (e) Baudoin, O.; Gueritte, R. In Studies in Natural Products
Hamel, E.; Wegrzynski, B.; Toome, V. Can. J. Chem. 1992, 70, 1237–1249.
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Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 2003; Vol. 29,
pp 355-417.
DOI: 10.1021/jo101953n
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Published on Web 11/08/2010
J. Org. Chem. 2010, 75, 8241–8251 8241
2010 American Chemical Society

Djurdjevic et al.
JOCArticle
groups are sufficiently nucleophilic for facile reaction.15 In
particular, given the propensity of propargyldicobalt cations
for reaction with electron-rich arenes and the demonstrated
ability of (Z)-arylalkene substituted propargyl acetate complexes
to react to form benzocycloheptyne-Co2(CO)6 complexes,12d
we considered the potential applicability of intramolecular
Nicholas reaction chemistry to dibenzocycloheptanes and
consequently allocolchicines to be highly promising. We
have reported on the viability of this approach in preliminary
form and now describe this chemistry in complete fashion.16
Results and Discussion
The general outline of the access to the 6,7,6-system was
envisioned to occur by construction of the Co2(CO)6 com-
plexes of biaryl-2-propargyl alcohol derivatives (8), which
would deliver dibenzocycloheptyne-Co2(CO)6 complexes (9)
in the presence of a Lewis acid. The former were prepared
in most instances by Suzuki-Miyaura coupling reactions
of arylboronic acids (10) with bromobenzaldehydes (11)
17
according the conditions employed by Furstner, giving
€
biaryl-2-carboxaldehydes (12a-f) in good yield (Scheme 1,
Table 1). These aldehydes were subjected to the Corey-
Fuchs protocol, with trapping of the resulting acetylide by
paraformaldehyde (Scheme 2). The resultant propargyl al-
cohols (13a-f) were formed in fair to good yields (56-80%)
except in the case of thienyl substituted 13d (40% yield); in
this case a significant amount of carbene insertion product 14
(53%) was formed competitively. Acetylation of 13a-f
under standard conditions and complexation with Co2(CO)8
then afforded 8a-f in good to excellent yields.
FIGURE 1. Common allocolchicines.
have seen synthesis by way of enyne metathesis/Diels-Alder
reactions ((-)-N-acetylcolchicine analogues),7 oxidative
coupling and copper-mediated cross-coupling ((-)-N-
acetylallocolchicinol),8 C-H activation reactions ((-)-allo-
colchicine formal synthesis),9 and aldol condensation chem-
istry ((-)-N-acetylallocolchicinol).8b,10 In addition, a recent
siloxane coupling/ring expansion reaction chemistry approach
to (()-NSC 51046 has been reported.11
Two additional substrates were prepared by procedures
other than the standard one. Unsubstituted 8g was obtained
by way of Sonogashira reaction between 2-iodobiphenyl and
The application of alkyne-Co2(CO)6 complexes in the
synthesis of seven-membered ring compounds has been
demonstrated by our group12 and by other groups,13 most
often based on Nicholas reaction chemistry. The reactions
are suited to seven-membered ring synthesis because com-
plexation of alkynes to Co2(CO)6 induces a change in bond
angle to ca. 140°,14 in that SN10 reactivity on the cationic
propargyldicobalt complex to give a five-membered ring
system does not occur, and since the electrophilicity of these
cations is such that arenes substituted with electron-donating
TABLE 1. Preparation of 8a-ga
10
11
12
13
8
10a
10a
10b
10c
10d
10a
11a
11b
11a
11a
11a
11c
12a (85)
12b (92)
12c (79)
12d (81)
12e (76)
12f (81)
13a (80)
13b (78)
13c (57)
13d (40)
13e (61)
13f (56)
8a (86)
8b (84)
8c (91)
8d (77)
8e (84)
8f (98)
aYields are in parentheses.
SCHEME 1. Suzuki-Miyaura Coupling Reactions
8242 J. Org. Chem. Vol. 75, No. 23, 2010

Djurdjevic et al.
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SCHEME 2. Preparation of Biaryl-2-propargyl Acetate-Co2(CO)6 Complexes (8)
SCHEME 3. Formation of 8g
propargyl alcohol to give 13g (87% yield) (Scheme 3), which
was in turn subjected to acetylation and complexation with
Co2(CO)8 under conditions analogous to 13a-f, affording
8g in 86% yield.
Carbomethoxy-substituted 8h, the propargyl ether-Co2-
(CO)6 complex envisioned as the precursor to allocolchicine
itself, required a modified approach for its preparation. In
this case, methyl 4-bromo-3-iodobenzoate, prepared by con-
ventional esterification of the corresponding acid,18 was
subjected to Sonogashira reaction with propargyl methyl
ether to afford 15 in 92% yield (Scheme 4). The Suzuki-
Miyaura reaction of this halide with 2,3,4-trimethoxyboro-
nic acid was somewhat problematic, as conventional condi-
tions resulted in predominant boronic acid hydrolysis and
recovery of substantial 15, with only a small amount of 16
SCHEME 4. Preparation of 8h
(7) (a) Boyer, F.-D; Hanna, I. Org. Lett. 2009, 9, 715–718. (b) Boyer,
F.-D; Hanna, I. Eur. J. Org. Chem. 2008, 4938–4948. (c) Boer, F.-D.; Dubois,
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isolated (27% yield). Use of Pd2(dba)3 with PCy3, however,
gave 16 in acceptable yield (53%, 77% based on recovered
starting material [brsm]), with recovery of 15 (31%). While most
of the material was carried forward using this protocol, it was
found ultimately that use of the PEPPSI-iPr catalyst enabled
formation of 16 in 79% yield.19 Formation of 8h was
accomplished from 16 in a straightforward manner (83%
yield) with Co2(CO)8.
(15) Kuhn, O.; Rau, D.; Mayr, H. J. Am. Chem. Soc. 1998, 120, 900–907.
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€
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1199.
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TABLE 2. Intramolecular Nicholas Reactions of 8
trimethoxy-substituted 8b, TLC analysis suggested the onset
of some decomposition without complete conversion at 16 h,
so that the reaction was terminated at this point and small
amount of 8b (10%) could be recovered in addition to the
isolated 9b (59% yield) (entry 3). 3-Thienyl-substituted 8d
underwent competitive cyclization at C-20 and C-40, afford-
ing 9d and 9d0 as a regioisomeric mixture (82%, 45:55
9d:9d0) (entry 5). It is also worthy of note that 8c f 9c
(entry 4) and 8g f 9g (entry 8) proceeded uneventfully, as the
less electron-rich arene nucleophiles would be of borderline
reactivity and insufficient reactivity, respectively, for parti-
cipation in intermolecular Nicholas reactions.15 Evidence of
restricted rotation about the aryl-aryl bond was present for
several of the cyclization products, as all dibenzocyclohep-
tyne-Co2(CO)6 complexes bearing an additional substituent
ortho to the biaryl gave diastereotopic CH2’s for the pro-
pargylic hydrogen atoms in the 1H NMR spectra (9a,b,f,g).
In addition, those bearing substitutents ortho to the cyclo-
heptyne either gave a diastereotopic CH2 (9c) or one right at
coalescence (9h).
Removal of the Co2(CO)6 fragment for use in synthesis
requires concomitant conversion of the alkyne function into
one compatible with the seven-membered ring.20,21 The most
commonly employed reagent for this purpose, Bu3SnH, has
caused some isomerization in related benzocycloheptyne
cases;12c consequently we chose to apply a modification of
Isobe’s hydrosilylation protocol20 that would afford the
alkene. Addition of triethylsilane to the dibenzocycloheptyne
complexes 9 in the presence of bis(trimethylsilylacetylene)
(BTMSE) gave a regioisomeric mixture of silylated cyclo-
heptenes, which were not isolated but subjected to in situ
desilylation with trifluoroacetic acid (TFA) to give the dibenzo-
cycloheptenes 17. These dibenzocycloheptenes (17a,e,f,h)
were isolated in good to excellent yields and with no evidence
of double bond isomerization during the reductive decom-
plexation process (Table 3).
Formal Synthesis of (-)-Allocolchicine. Since several of the
existing syntheses of allocolchicines employ the dibenzocy-
cloheptanones (18) as critical intermediates, conversion of
dibenzocycloheptenes 17 to 18 was considered to be the most
prudent approach toward their synthesis. Hydroboration-
oxidation of 17h with BH3-THF/H2O2, with further oxida-
tion of the intermediate alcohol using PDC, afforded ketone
18h in good yield (81%). Dibenzocycloheptanone 18h has
been converted to (-)-allocolchine by Wulff,6 and as such
this represents a formal synthesis of this natural product.
Similarly, treatment of 17f by BH3-THF/H2O2 followed
by oxidation with PDC afforded 18f (67% yield). Dibenzo-
cycloheptanone 18f is a degradation product of (-)-andro-
biphenyline that has been prepared previously by Seitz,22
and found to be equally potent as (-)-androbiphenyline in
inhibition of tubulin assembly.
entry
8
time (h)
9
yield (%)
1
2
3
4
5
6
7
8
9
8a
8a
8b
8c
8d
8e
8f
2.5
6
16
6
9a
9a
9b
9c
9d
9e
9f
56a
71
59 (66)b
85
5
82c
91
83
58
4.5
4.5
16
5
8g
8h
9g
9h
84
aNo i-Pr2NEt added. bYields in parentheses based on recovered
starting material. cIsolated as a 45:55 9d:9d0 mixture.
With the Nicholas reaction precursors in hand, attention
was turned to investigation of the cyclizations. Under con-
ditions developed previously for benzocycloheptyne ring-
closure reactions, 8a (0.005 M in CH2Cl2) underwent reac-
tion in the presence of BF3-OEt2 (3 equiv), giving dibenzo-
cycloheptyne 9a over 2.5 h (56% yield) (Table 2, entry 1). As
a small amount of decomposition was evident chromatogra-
phically during this process, and with the belief that this
could be due to the acid liberated during the substitution
process, the reaction was conducted with the addition of 1.5
equiv of i-Pr2NEt. Although the reaction occurred some-
what more slowly (6 h) (entry 2), 9a could be isolated in
improved yield (71%). These conditions (3 equiv of
BF3-OEt2, 1.5 equiv of i-Pr2NEt, 0.005-0.01 M) were
applied to 8b-8h (Table 2) and afforded fair to excellent
yields of 9b-h. While there was some variation in required
reaction time (4.5-16 h) and substrate, there was no parti-
cular correlation between reaction time and substitution
pattern of the arene behaving as nucleophile. In the case of
Synthesis of (-)-N-Acetylcolchicine O-Methyl Ether (NSC
51046) and Analogue. Conversion of 17a to ketone 18a was
accomplished by hydroboration-oxidation with further
(20) For other reductive decomplexation reactions, see: (a) Hosokawa, S.;
Isobe, M. Tetrahedron Lett. 1998, 39, 2609–2612. (b) Takai, S.; Ploypradith, P.;
Hamajima, A.; Kira, K.;Isobe, M. Synlett2002, 588–592. (c) Isobe, M.; Yenjai,
C.; Tanaka, S. Synlett 1994, 916–918.
(21) Kira, K.; Tanda, H.; Hamajima, A.; Baba, T.; Takai, S.; Isobe, M.
Tetrahedron 2002, 58, 6485–6492.
(22) Brecht, R.; Seitz, G.; Guenard, D.; Thoret, S. Bioorg. Med. Chem.
2000, 8, 557–562.
(19) O’Brien, C. J.; Kantchev, E. A. B.; Valente, C.; Hadei, N.; Chass,
G. A.; Lough, A.; Hopkinson, A. C.; Organ, M. G. Chem.;Eur. J. 2006, 12,
4743–4748.
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TABLE 3. Conversion of 9 to Dibenzocycloheptanones 18
SCHEME 5. Completion of Enantioselective Synthesis of NSC
51046 and Its 3,8,9,10-Tetramethoxy Isomer
In summary, intramolecular Nicholas reactions have pro-
ven to be effective in the synthesis of dibenzocycloheptyne-
Co2(CO)6 complexes. Ready decomplexation to the diben-
zocycloheptenes allows application of this methodology to
the synthesis of allocolchicines or their derivatives, including
tubulin-inhibiting ketone 6,7-dihydro-3,4,9,10,11-penta-
methoxy-5H-dibenzo[a,c]cyclohepten-5-one (18f), a formal
total synthesis of (-)-allocolchicine (1), the enantioselective
total synthesis of N-acetylallocolchinol O-methyl ether
(NSC 51046, 2), and of the 3,8,9,10- tetramethoxy isomer
of NSC 51046 (21).
9
17
yield (%)
18
yield (%)
9a
9e
9f
17a
17e
17f
17h
97
94
90
79
18a
18e
18f
18h
80a
68
67
81
9h
aOxidation under Swern conditions (oxalyl chloride-DMSO, Et3N).
oxidation under Swern conditions (DMSO-oxalyl chloride,
Et3N), giving the ketone in 80% yield. Adopting the approach of
Wulff’s group toward (-)-allocolchicine, the reduction of
ketone 18a using the LiBH4/tartrate derived boronate ester
(TARB-NO2) protocol of Singaram23 gave alcohol 19a in
excellent yield and enantioselectivity (96% yield, 95% ee)
(Scheme 5). Substitution of azide for the alcohol function by
way of zinc azide/diisoproyl azodicarboxylate (DIAD)24
afforded 20a (64%), while azide reduction (H2, Lindlar
catalyst) of 20a and acetylation gave NSC 51046 (2) in
88% (93% ee), which was spectroscopically identical to
literature report.11 Recrystallization of 2 gave this com-
pound in >99% ee. To our knowledge this is the first
asymmetric synthesis of 2.
Similarly, dibenzocycloheptene 17e was converted to an
isomeric 3,8,9,10-tetramethoxyallocolchicine (21). Hydro-
boration-oxidation of 17e and further oxidation with PDC
afforded dibenzocycloheptanone 18e in 68% yield. LiBH4/
TARB-NO2 based reduction afforded the highly enantio-
merically enriched alcohol 19e (98% yield, 98% ee) provided
an extended period of substrate/TARB-NO2 mixing and
slow LiBH4 addition protocol was followed.25 Zinc azide
based substitution of the alcohol afforded 20e without
incident (77% yield), while reduction and acetylation gave
21 in 79% yield (95% ee); once again, a single recrystalliza-
tion enriched this compound to >99% ee. To our knowl-
edge, this is the first example of an allocolchicine with an
8,9,10-oxygenated A ring.
Experimental Section
General Methods. All reaction solvents were used after pas-
sage through a solvent purification system. Commercial BF3-
OEt2 was distilled and stored under nitrogen. All reactions were
conducted under a nitrogen atmosphere unless otherwise noted.
Flash chromatography was performed as described by Still
using silica gel 60 (230-400 mesh).26 2-Bromo-5-methoxybenzal-
dehyde27 and 6-bromo-2,3-dimethoxybenzaldehyde28 were pre-
pared by literature methods and were >95% purity as deter-
1
mined by H and 13C NMR spectroscopy. All new compounds
1
were >95% purity as determined by H and 13C NMR spec-
troscopy. NMR spectra were run at 500 or 300 MHz for 1H and
125 or 75 MHz for 13C in CDCl3; chemical shifts are given in
ppm and coupling constants (J) are given in Hz. High resolution
mass spectra were run by time-of-flight mass spectroscopy, in EI
mode, at 70 eV.
20,30,4,40-Tetramethoxy[1,10-biphenyl]-2-carboxaldehyde (12a).
Prepared according to the method of Furstner,17 11a (0.3517 g,
€
1.16 mmol) afforded 7a (0.4202, 85%): mp 102-3 °C (hexanes);
lit.17 102-3 °C. This compound was >95% purity as determined
by 1H and 13C NMR spectroscopy.
20,30,40-Trimethoxy[1,10-biphenyl]-2-carboxaldehyde (12b).
17
Prepared according to the method of Furstner, 11b (0.2278 g,
€
1.23 mmol) affording 12b (0.3706 g, 92%): mp 105-5.5 °C
(hexanes); lit.17 98-99 °C. This compound was >95% purity
as determined by 1H and 13C NMR spectroscopy.
4-Methoxy-30,50-dimethyl[1,10-biphenyl]-2-carboxaldehyde (12c).
Prepared as adapted from the method of Furstner,17 employing 11a
(0.9593 g, 4.46 mmol) and (3,5-dimethylphenyl)boronic acid (6b)
€
(23) (a) Suri, J. T.; Vu, T.; Hernandez, A.; Congdon, J.; Singaram, B.
Tetrahedron Lett. 2002, 43, 3649–3652. (b) Cordes, D. B.; Nguyen, T. M.;
Kwong, T. J.; Suri, J. T.; Luibrand, R. T.; Singaram, B. Eur. J. Org. Chem.
2005, 5289–5295.
(26) Still, W. C.; M. Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923–
2925.
(27) Bianchi, D. A.; Cipulli, M. A.; Kaufman, T. S. Eur. J. Org. Chem.
2003, 4731–4736.
(24) Viaud, M. C.; Rollin, P. Synthesis 1990, 130–132.
(25) Rapid addition of LiBH4 afforded 19b in ca. 50% ee.
(28) Kessar, S. V.; Gupta, V. P.; Balakrishnan, P.; Sawal, K. K.;
Mohammad, T.; Dutt, M. J. Org. Chem. 2003, 53, 1708–1713.
J. Org. Chem. Vol. 75, No. 23, 2010 8245

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(1.3423 g, 8.96 mmol) to give 12c (0.8472 g, 79% yield), following
flash chromatographic purification (15:1 petroleum ether/Et2O), as
a colorless viscous oil which solidified upon standing: mp 71-2 °C;
IR(KBr) νmax 3006, 2917, 1688, 1604 cm-1;1 HNMRδ9.97 (s, 1H),
7.52 (d, J=2.8, 1H), 7.37 (d, J=8.5, 1H), 7.19 (dd, J=8.5, 2.8, 1H),
7.06 (br s, 1H), 6.97 (br s, 2H), 3.90 (s, 3H), 2.39 (s, 6H); 13C NMR
192.4, 159.0, 139.4, 137.9, 137.4, 134.5, 131.9, 129.3, 128.1, 121.2,
109.7, 55.5, 21.2; MS m/e240 (Mþ);HRMSm/efor C16H16O2 calcd
240.1150 (Mþ), found 240.1140.
61.0, 60.9, 55.9, 55.3, 51.4; MS m/e 328 (Mþ); HRMS m/e for
C19H20O5 calcd 328.1311 (Mþ), found 328.1311 .
3-(20,30,40-Trimethoxybiphenyl-2-yl)-2-propyn-1-ol (13b).Reaction
of aldehyde 12b (0.1514 g, 0.554 mmol) according to General
Procedure A afforded 13b (0.1293 g, 78% yield) following prepara-
tive TLC (1:2 hexanes/Et2O), as a viscous oil: IR (KBr) νmax 3379 br,
2933, 2227 cm-1;1 HNMRδ7.52 (dd, J=7.7, 1.0, 1H), 7.25-7.37 (m,
3H), 6.98 (d, J=8.5, 1H), 6.71 (d, J=8.6, 1H), 4.29 (s, 2H), 3.91 (s,
3H), 3.91 (s, 3H), 3.63 (s, 3H), 2.07 (br, 1H); 13C NMR 153.3, 151.5,
142.0, 140.8, 132.3, 130.2, 128.0, 127.5, 126.9, 125.3, 122.4, 106.8,
89.9, 85.2, 61.0, 60.9, 56.0, 51.4; MS m/e 298 (Mþ); HRMS m/e for
C18H18O4 calcd 298.1205 (Mþ), found 298.1201.
5-Methoxy-2-(3-thienyl)benzaldehyde (12d). Prepared as adapted
€
17
from the method of Furstner, employing 11a (0.2301 g,
1.07 mmol) and 3-thienylboronic acid (10c) (0.2003 g, 1.56 mmol)
to give 12d (0.1900 g, 81% yield) following flash chromatographic
purification (15:1 petroleum ether/Et2O): mp 68-69 °C (CH2Cl2);
(3-Methoxy-30,50-dimethylbiphenyl-2-yl)-2-propyn-1-ol (13c).
Reaction of aldehyde 12c (0.8472 g, 3.53 mmol) according to
General Procedure A afforded 13c (0.5389 g, 57% yield) follow-
ing flash chromatography (2:1 petroleum ether/Et2O) as a
IR (KBr) νmax 3100, 2845, 1684 cm-1 1 H NMR δ 10.08 (s, 1H),
;
7.50 (d, J=2.7, 1H), 7.44 (dd, J=4.8, 3.0, 1H), 7.41 (d, J=8.5, 1H),
7.24 (dd, J=3.0, 0.9, 1H), 7.19 (dd, J =8.5, 2.7, 1H), 7.17 (dd, J=
4.8, 0.9, 1H), 3.90 (s, 3H); 13C NMR 192.2, 159.0, 137.9, 134.7,
133.5, 131.8, 129.4, 126.1, 124.5, 121.5, 109.7, 55.5; MS m/e 218
(Mþ); HRMS m/e for C12H10O2S calcd 218.0402 (Mþ), found
218.0399.
viscous oil: IR (KBr) νmax 3400 br, 2917, 1603 cm-1 1 H NMR
;
δ7.31 (d, J=8.5, 1H), 7.20 (s, 2H), 7.08 (d, J=2.8, 1H), 7.00 (s, 1H),
6.96 (dd, J=8.5, 2.7, 1H), 4.37 (s, 2H), 3.84 (s, 3H), 2.38 (s, 6H), 1.55
(br, 1H) ; 13C NMR 158.3, 140.0, 137.3, 136.9, 130.6, 128.7, 127.1,
121.6, 117.4, 115.4, 89.8, 85.6, 55.4, 51.6, 21.3; MS m/e 266
(Mþ); HRMS m/e for C18H18O2 calcd 266.1307 (Mþ), found
266.1294.
30,4,40,50-Tetramethoxy[1,10-biphenyl]-2-carboxaldehyde (12e).
Prepared according to the method of Furstner17 employing 11a
€
(0.7000 g, 3.26 mmol) and 3,4,5-trimethoxyphenylboronic acid
(10d) (1.0877 g, 4.89 mmol) to give 12e (0.7472 g, 76% yield)
following flash chromatographic purification (3:1 petroleum
ether/Et2O), as a colorless solid: mp 134-136 °C; IR (KBr)
3-(5-Methoxy-2-(3-thienyl)phenyl)-2-propyn-1-ol (13d) and
7-Methoxynaphtho[2,1-b]thiophene (14). Reaction of aldehyde 12d
(0.0876 g, 0.401 mmol) according to General Procedure A gave, in
order of elution, 14 (0.0452 g, 53% yield) and 13d (0.0389 g, 40%
yield), following preparative TLC (1:1 petroleum ether/Et2O). 14 as a
colorless solid: mp 118-120 °C; IR (KBr) νmax 2956, 1621 cm-1; 1H
NMR δ 8.26 (d, J=8.8, 1H), 7.92 (d, J=5.4, 1H), 7.87 (d, J=
8.7, 1H), 7.67 (d, J=8.7, 1H), 7.58 (d, J=5.4, 1H), 72.6-7.31 (m,
2H), 3.97 (s, 3H); 13C NMR 157.2, 136.1, 135.4, 132.2, 125.9, 125.1,
124.5, 124.3, 121.7, 121.2, 118.0, 107.6, 55.4; MS m/e 214 (Mþ);
HRMS for C13H10O2S (Mþ) calcd 214.0452, found 214.0454. 13d as
1
2931, 1687, 1604 cm-1; H NMR δ 9.96 (s, 1H), 7.47 (d, J =
2.8, 1H), 7.37 (d, J=8.5, 1H), 7.17 (dd, J=8.5, 2.8, 1H), 6.52 (s,
2H), 3.89 (s, 3H), 3.88 (s, 3H), 3.87 (s, 6H); 13C NMR 192.2,
159.1, 152.9, 139.0, 137.7, 134.5, 133.1, 131.7, 121.2, 109.8, 107.5,
60.9, 56.2, 55.5; MS m/e (Mþ) 302; HRMS m/e for C17H18O5
calcd 302.1154, found 302.1139.
20,3,30,4,40-Pentamethoxy[1,10-biphenyl]-2-carboxaldehyde (12f).
17
Prepared according to the method of Furstner employing 11c
a viscous oil: IR (KBr) νmax 3384 br, 2928, 2228 cm-1 1 H NMR δ
;
€
(0.7937 g, 3.24 mmol) and 2,3,4-trimethoxyphenylboronic acid
(10a) (1.0993 g, 5.18 mmol) to give 12f (0.8712 g, 81% yield)
following flash chromatographic purification (4:1 petroleum ether/
7.54 (dd, J=3.0, 1.4, 1H), 7.42 (dd, J=5.0, 1.4, 1H), 7.34 (d, J=
8.6, 1H), 7.34 (dd, J=5.0, 3.0, 1H), 7.06 (d, J=2.7, 1H), 6.93 (dd, J=
8.6, 2.7,1H) 4.46 (d, J=4.2, 2H), 3.84 (s, 3H), 1.61 (br, 1H); 13C
NMR 158.2, 140.5, 131.2, 130.2, 128.5, 124.7, 122.6, 121.2, 117.7,
115.6, 90.2, 85.7, 55.4, 51.8; MS m/e 244 (Mþ); HRMS m/e for
C14H12O2S calcd 244.0558 (Mþ), found 244.0550.
3-(30,4,40,50-Tetramethoxybiphenyl-2-yl)-2-propyn-1-ol (13e).
Reaction of aldehyde 12e (0.4674 g, 1.55 mmol) according to
General Procedure A gave 13e (0.3115 g, 61% yield), following
flash chromatography (1:1 petroleum ether/Et2O), as a viscous
oil: IR (KBr) 3500 br, 2935, 2224, 1602 cm-1; 1H NMR δ 7.29 (d,
J=8.6, 1H), 7.06 (d, J=2.7, 1H), 6.92 (dd, J=8.6, 2.7, 1H), 6.79
(s, 2H), 4.38 (s, 2H), 3.88 (s, 3H), 3.87 (s, 6H), 3.81 (s, 3H), 2.33
(br s, 1H); 13C NMR 158.1, 152.5, 137.0, 136.1, 135.4, 130.3,
121.3, 117.6, 115.2, 106.4, 90.3, 84.8, 60.7, 56.0, 55.2, 51.2; MS
m/e (Mþ) 328; HRMS m/e for C19H20O5 calcd 328.1311, found
328.1308.
3-(203,30,4,40-Pentamethoxybiphenyl-2-yl)-2-propyn-1-ol (13f).
Reaction of aldehyde 12f (0.8629 g, 2.60 mmol) according to
General Procedure A gave 13f (0.5257 g, 56% yield), flash
chromatography (1:1 hexanes/Et2O), as a viscous oil: IR (KBr)
3509 br, 2936, 2227, 1591 cm-1; 1H NMR δ 6.96 (d, J=8.5, 1H),
6.91 (d, J=8.6, 1H), 6.88 (d, J=8.5, 1H), 6.64 (d, J=8.6, 1H),
4.28 (br d, J=4.8, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.83
(s, 3H), 3.61 (s, 3H), 2.88 (br, 1H); 13C NMR 152.8, 151.24,
151.17, 149.9, 141.6, 133.9, 126.7, 125.4, 125.3, 117.4, 112.0,
106.4, 94.3, 80.3, 60.7, 60.61, 60.57, 55.6, 51.0; MS m/e 358 (Mþ);
HRMS m/e for C20H22O6 calcd 358.1416, found 358.1404.
3-Biphenyl-2-yl-2-propyn-1-ol (13g). To a solution of 20-iodo-
biphenyl (0.10 mL, 0.57 mmol), Pd(PPh3)4 (10 mg), and CuI (20
mg) in degassed diisopropylamine (5 mL) was added propargyl
alcohol (0.15 mL, 2.6 mmol). After 20 h of stirring, the volatiles
were removed under reduced pressure, the residue was filtered
EtOAc): mp 117-119 °C; IR (KBr) νmax 2938, 1699, 1593 cm-1
;
1H NMR δ 10.15 (s, 1H), 7.12 (d, J=8.4, 1H), 7.01 (d, J=8.4, 1H),
6.87 (d, J=8.5, 1H), 6.71 (d, J=8.5, 1H), 3.96 (s, 3H), 3.93 (s, 3H),
3.890 (s, 3H), 3.887 (s, 3H), 3.58 (s, 3H); 13C NMR 191.1, 153.2,
152.0, 150.5, 149.9, 141.7, 131.7, 129.0, 126.6, 125.7, 124.5, 115.9,
106.9, 61.7, 60.7, 60.3, 55.74, 55.68; MS m/e 332 (Mþ); HRMS for
C18H20O6 (Mþ) calcd 332.1260, found 332.1275.
3-(20,30,4,40-Tetramethoxybiphenyl-2-yl)-2-propyn-1-ol (13a).
General Procedure A. To a solution of 12a (0.3378 g, 1.12 mmol)
in CH2Cl2 (10 mL) were added CBr4 (0.556 g, 1.68 mmol) and
PPh3 (1.172 g, 4.47 mmol). After 4 h of stirring, petroleum ether
(10 mL) and iodomethane (0.4 mL) were added, and the mixture
was allowed to stir for 8 h. The volatiles were removed under
reduced pressure, and the residue filtered through silica gel,
using 1:1 petroleum ether/Et2O as solvent). The filtrate was
concentrated under reduced pressure to give the crude dibro-
mide, which was used without further purification. The dibro-
mide was dissolved in THF (20 mL) and cooled to -78 °C.
Butyllithium (1.08 mL of a 2.58 M solution in hexanes, 2.79
mmol) was added, and stirring was continued for 5 h. A
suspension of paraformaldehyde (0.4 g, excess) in THF (5 mL)
was added, and the reaction was stirred for 8 h as the mixture
gradually warmed to room temperature. A conventional extractive
workup followed by flash chromatography (1:2 petroleum ether/
Et2O) gave 13a (0.2919 g, 80%), as a viscous oil: IR (KBr) νmax
3455 br, 2937, 2229 cm-1; 1 H NMR δ 7.22 (d, J=8.6, 1H), 7.05 (d,
J=2.7, 1H), 6.96 (d, J=8.5, 1H), 6.91 (dd, J=8.6, 2.7, 1H), 6.68
(dd, J=8.5, 1H), 4.29 (s, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.82 (s, 3H),
3.61 (s, 3H), 2.30 (br, 1H) ; 13C NMR 158.2, 153.1, 151.6, 142.0,
133.3, 131.3, 127.1, 125.6, 123.2, 116.8, 114.8, 106.7, 89.6, 85.2,
8246 J. Org. Chem. Vol. 75, No. 23, 2010

Djurdjevic et al.
JOCArticle
through silica with Et2O, and the volatiles were again removed
in vacuo. Preparative TLC in 2:1 hexanes/Et2O gave 0.1025 g of
13g (87% yield): bp 135-140 °C (0.15 Torr) (bulb-to-bulb); IR
(KBr) νmax 3054, 3061, 2925, 2235 cm-1; 1 H NMR δ 7.58 (d, J=
7.3, 2H), 7.57 (d, J = 7.9, 1H), 7.44 (apparent t, Jave=7.5, 2H),
(excess) was added, and the mixture was stirred 4 h. After con-
centration under reduced pressure, flash chromatography (100%
petroleum ether f 5:1 petroleum ether/Et2O) gave acetate complex
8a (0.4952 g, 86% yield) as a red-brown solid: mp 122-124 °C ; IR
(KBr)νmax 2919, 2090, 2050, 2018, 1743 cm-1; 1 H NMRδ7.30 (d,
J=2.5, 1H), 7.00 (d, J = 8.5, 1H), 6.88 (dd, J = 8.5, 2.5, 1H), 6.80
(d,J=8.5, 1H), 6.73 (d, J= 8.5, 1H), 4.58 (d, J= 15.0, 1H), 3.97 (d,
J = 15.0, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.86 (s, 3H), 3.59 (s, 3H),
2.02 (s, 3H); 13C NMR 199.4, 199.3, 170.3, 159.2, 153.9, 151.2,
142.4, 137.6, 131.8, 129.4, 128.2, 125.4, 118.0, 114.5, 107.3, 92.5,
88.7, 64.4, 60.7, 60.4, 56.2, 55.0, 20.2 ; MS m/e600 (Mþ - 2CO), 572
(Mþ - 3CO), 488 (Mþ - 6CO). Anal. Calcd for C27H22Co2O12 C,
49.41; H, 3.38. Found: C, 49.68; H, 3.38.
7.35-7.41 (m, 3H), 7,31 (m, 1H), 4.35 (s, 2H), 1.63 (br s, 1H); 13
C
NMR (40 °C) 144.0, 140.5, 133.1, 129.5, 129.2, 128.6, 127.9,
127.4, 127.0, 121.0, 90.2, 85.4, 51.5; MS m/e 208 (Mþ); HRMS
m/e for C15H12O calcd 208.0888 (Mþ), found 208.0890.
Methyl 4-Bromo-3-iodobenzoate. To a solution of 4-bromo-3-
iodobenzoic acid (1.3227 g, 3.68 mmol) in methanol (40 mL) was
added H2SO4 (10 drops). The mixture was heated to reflux for 12 h.
Following a conventional extractive workup (Et2O) and extrac-
tion of the Et2O layers with NaOH(aq), the Et2O layers were dried
over MgSO4, filtered, and concentrated under reduced pressure.
Flash chromatography (8:1 petroleum ether/Et2O) afforded
methyl 4-bromo-3-iodobenzoate (1.2550 g, 91% yield) as a
Hexacarbonyl[μ-η4-(3-acetoxy-(20,30,40-trimethoxybiphenyl-
2-yl)-1-propyne]dicobalt (8b). Subjecting 13b (0.1214 g, 0.407
mmol) to General Procedure B afforded 18b (0.2140 g, 84%
yield) following flash chromatographic purification (10:1 f
4:1 petroleum ether/Et2O), as a red-brown solid: mp 108-
colorless solid: mp 70-71 °C; IR (KBr) νmax 3087, 1726 cm-1
;
1H NMR δ 8.46 (s, 1H), 7.81 (d, J=8.2, 1H), 7.66 (d, J=8.2, 1H),
3.90 (s, 3H); 13C NMR 164.8, 141.1, 135.2, 132.5, 130.12, 130.08,
101.0, 52.5; MS m/e (Mþ) 340/342; HRMS m/e for C8H6BrIO2
calcd 339.8596, found 339.8603.
110 °C; IR (KBr) νmax 2938, 2090, 2052, 2022, 1745 cm-1 1 H
;
NMR δ 7.76 (d, J=7.8, 1H), 7.40 (apparent t, J=7.4, 1H), 7.31
(apparentt,J=7.3, 1H), 7.11 (d, J= 7.5, 1H), 6.82 (d, J=8.4, 1H),
6.75 (d, J=8.4, 1H), 4.59 (d, J=14.5, 1H), 3.98 (d, J=14.5, 1H),
3.98 (s, 3H), 3.94 (s, 3H), 3.60 (s, 3H), 2.03 (s, 3H); 13C NMR
199.3, 170.4, 154.1, 151.5, 142.6, 137.1, 136.6, 134.3, 130.9,
128.6, 128.1, 127.4, 125.0, 107.5, 92.6, 88.6, 64.6, 60.8, 60.5,
56.4. 20.2 ; MS m/e 570 (Mþ - 2CO), 542 (Mþ - 3CO), 458
Methyl 4-Bromo-3-(3-methoxyprop-1-ynyl)benzoate (15). To a
solution of methyl 4-bromo-3-iodobenzoate (1.255 g, 3.21 mmol)
and propargyl methyl ether (0.47 mL, 5.9 mmol) in diisopropyla-
mine (5 mL) were added CuI (0.0404 g, 0.212 mmol) and Pd-
(PPh3)4 (0.070 g, 0.061 mmol). After 12 h of stirring, the mixture
was subjected to a conventional extractive workup. Flash chro-
matography (5:1 petroleum ether/Et2O) afforded 15 (0.9599 g,
92% yield) as yellow crystals: mp 42-43 °C; IR (KBr) νmax 3033,
2953, 1739, 1593 cm-1; 1H NMR δ 8.10 (d, J=2.0, 1H), 7.78 (dd,
J=8.4, 2.0, 1H), 7.64(d, J=8.4, 1H), 4.37 (s, 2H), 3.89 (s, 3H), 3.48
(s, 3H); 13C NMR 165.6, 134.4, 132.5, 130.6, 130.1, 129.2, 125.2,
90.7, 84.0, 60.2, 57.7, 52.3; MS m/e 282/284 (Mþ); HRMS for
C12H11BrO3 calcd 283.9891, found 283.9900.
(Mþ - 6CO); HRMS for C26H20Co2O11 calcd 597.9720 (Mþ
CO), found 597.9741.
-
Hexacarbonyl[μ-η4-(3-acetoxy-(3-methoxy-30,50-dimethylbi-
phenyl-2-yl)-1-propyne]dicobalt (8c). Subjecting 13c (0.0608 g,
0.228 mmol) to General Procedure B afforded acetate complex
8c (0.1232 g, 91% yield) of acetate complex (91% yield)
following flash chromatography (10:1 petroleum ether/Et2O),
as a red-brown solid: mp 250 °C (dec); IR (KBr) νmax 2961,
2090, 2058, 1998, 1748 cm-1; 1 H NMR δ 7.28 (d, J = 2.7, 1H),
7.08 (s, 1H), 7.04 (d, J = 8.4, 1H), 6.89 (dd, J = 8.4, 2.7, 1H),
6.86 (s, 2H), 4.02 (s, 2H), 3.87 (s, 3H), 2.37 (s, 6H), 2.04 (s, 3H);
13C NMR 199.4, 170.4, 159.2, 141.6, 138.2, 136.4, 134.2, 131.1,
129.2, 127.4, 118.0, 114.6, 93.3, 88.9, 64.2, 55.2, 21.1, 20.3; MS
m/e 566 (Mþ - CO), 510 (Mþ - 3CO), 426 (Mþ - 6CO);
HRMS m/e for C26H20Co2O9 calcd 565.9822 (Mþ - CO),
found 565.9811.
Methyl 20,30,40-Trimethoxy-2-(3-methoxyprop-1-ynyl)biphenyl-
4-carboxylate (16). A mixture of methyl 4-bromo-3-(3-methox-
yprop-1-ynyl)benzoate (15) (0.0712 g, 0.251 mmol), 2,3,4-tri-
methoxyphenylboronic acid (10a) (0.1333 g, 0.629 mmol), K3PO4
(0.1590 g, 0.750 mmol), Pd2(dba)3 (0.0046 g, 0.0050 mmol), and
PCy3 (0.0035 g, 0.012 mmol) in toluene (10 mL) was heated to
100 °C for 37 h. Following an extractive workup, radial chroma-
tography (5:1 petroleum ether/Et2O) afforded, in order of elu-
tion, recovered 15 (0.0218 g, 31% recovery), and 16 (0.0493 g,
Hexacarbonyl[μ-η4-(3-acetoxy-1-(5-methoxy-2-(3-thienyl)phenyl)-
1-propyne]dicobalt (8d). Subjecting 13d (0.0418 g, 0.171 mmol)
to General Procedure B gave acetate complex 8d (0.0756, 77%
yield) following flash chromatography (10:1 petroleum ether/
Et2O), as a red-brown solid: mp 104-105 °C; IR (KBr) νmax
53% yield) as a viscous oil: IR (KBr) νmax 2936, 1730, 1605 cm-1
;
1H NMR δ 8.22 (d, J = 1.8, 1H), 8.00 (dd, J = 8.1, 1.8, 1H), 7.41
(d, J = 8.1, 1H), 7.01 (d, J = 8.5, 1H), 6.72 (d, J = 8.5, 1H), 4.20
(s, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.91 (s, 3H), 3.66 (s, 3H), 3.23 (s,
3H); 13C NMR 166.4, 153.8. 151.4, 145.3, 142.1, 133.7, 130.6,
128.9, 126.6, 125.2, 122.9, 106.7, 88.2, 85.2, 61.2, 61.0, 60.2, 57.2,
56.1, 52.2; MS m/e 370 (Mþ); HRMS for C21H22O6 (Mþ) calcd
370.1416, found 370.1416.
2941, 2090, 2055, 2021, 1745 cm-1 1 H NMR δ 7.46 (dd, J =
;
4.7, 3.1, 1H), 7.28 (d, J = 2.6, 1H), 7.15 (m, 1H), 7.06 (d, J =
8.4, 1H), 7.02 (d, J = 4.7, 1H), 6.88 (dd, J = 8.4, 2.6, 1H), 4.30
(s, 2H), 3.87 (s, 3H), 2.05 (s, 3H); 13C NMR 199.3, 170.5, 159.6,
141.9, 137.2, 131.8, 130.1, 128.3, 126.1, 123.8, 118.3, 114.7,
93.1, 88.4, 63.9, 55.2, 20.3; MS m/e 544 (Mþ - CO), 488 (Mþ -
3CO), 404 (Mþ - 6CO); HRMS m/e for C22H14Co2O9S calcd
543.9073 (Mþ -CO), found 543.9078.
A solution of potassium tert-butoxide (0.0351 g, 0.314 mmol)
and (1,3-diisopropylimiazol-2-ylidene)(3-chloropyridyl)palladium-
(II) dichloride (0.0014 g, 1 mol %) in isopropanol (1 mL) was
stirred for 10 min. To this solution was added 2,3,4-trimethoxy-
phenylboronic acid (10a) (0.0975 g, 0.460 mmol) and 15 (0.0590 g,
0.209 mmol). After stirring for 12 h, diethyl ether was added, and
reaction was subjected to a conventional extractive workup (Et2O).
Preparative TLC (5:1 petroleum ether/Et2O) afforded 16 (0.0612 g,
79% yield).
Hexacarbonyl[μ-η4-(3-acetoxy-(,30,4,40,50-tetramethoxybiphenyl-
2-yl)-1-propyne)]dicobalt (8e). Subjecting 13e (0.2809 g, 0.855
mmol) to General Procedure B afforded 8e (0.4722 g, 84%
yield) following flash chromatographic purification (3:1 pe-
troleum ether/Et2O), as a red-brown solid: mp 126-128 °C; IR
(KBr) νmax 2938, 2090, 2010, 1974, 1748 cm-1; 1H NMR δ 7.27
(d, J = 2.6, 1H), 7.05 (d, J = 8.4, 1H), 6.89 (dd, J = 8.4, 2.6,
1H), 6.42 (s, 2H), 4.22 (s, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 3.82 (s,
6H), 2.02 (s, 3H); 13C NMR 199.3, 170.3, 159.4, 153.2, 137.7,
137.3, 136.4, 133.6, 131.2, 117.7, 114.7, 106.9, 93.1, 88.3, 63.9,
Hexacarbonyl[μ-η4-(3-acetoxy-(20,30,4,40-tetramethoxybiphe-
nyl-2-yl)-1-propyne)]dicobalt (8a). General Procedure B. To
alcohol 13a (0.2875 g, 0.876 mmol) at 0 °C were added acetic
anhydride (1 mL) and pyridine (1 mL). The solution was stirred 4 h,
as the solution came to room temperature. The volatiles were
removed under reduced pressure, and the residue was dissolved in
CH2Cl2 (25 mL). An unweighed amount of octacarbonyldicobalt
61.1, 56.1, 55.1, 20.2; MS m/e 628 (Mþ - CO), 600 (Mþ
-
2CO), 572 (Mþ - 3CO), 544 (Mþ - 4CO), 516 (Mþ - 5CO),
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Djurdjevic et al.
JOCArticle
488 (Mþ - 6CO); HRMS for C27H22Co2O12 calcd (Mþ - CO)
627.9826, found 627.9802.
0.135 mmol) to General Procedure C (16 h), followed by flash
chromatography (5:1 petroleum ether/Et2O) afforded 9b
(0.0452 g, 59% yield, 66% yield based on recovered starting
material) followed by recovered 8b (0.0085 g, 10% recovery).
9b: red-brown solid, mp 116-118 °C; IR (KBr) νmax 3057, 2934,
2090, 2051 cm-1; 1 H NMR δ 7.69 (dd, J=7.4, 1.3, 1H), 7.63 (dd,
J = 7.6, 1.3, 1H), 7.38 (apparent dt, J = 1.3, 7.4, 1H), 7.35
(apparent dt, J=1.3, 7.6, 1H), 6.67 (s, 1H), 4.03 (d, J=14.0, 1H),
Hexacarbonyl[μ-η4-(3-acetoxy-(20,3,30,4,40-pentamethoxy-
biphenyl-2-yl)-1-propyne)]dicobalt (8f). Subjecting 13f (0.5231
g, 1.46 mmol) to General Procedure B afforded 8f (0.9818 g,
98% yield) following flash chromatographic purification (4:1
petroleum ether/Et2O), as a red-brown solid: mp 120-121 °C;
IR (KBr) νmax 3002, 2939, 2088, 2009, 1743 cm-1; 1H NMR δ
6.95 (d, J=8.4, 1H), 6.80 (d, J=8.4, 1H), 6.73 (d, J=8.4, 1H),
6.71 (d, J = 8.4, 1H), 4.53 (d, J = 14.5, 1H), 4.07 (s, 3H), 3.95
(s, 3H), 3.92 (s, 3H), 3.90 (s, 3H), 3.83 (d, J = 14.5, 1H), 3.61
(s, 3H), 2.00 (s, 3H); 13C NMR 199.8, 170.4, 153.9, 151.6,
151.4, 149.5, 142.4, 131.3, 128.84, 128.79, 125.6, 125.4, 112.2,
107.2, 94.3, 81.0, 65.4, 60.6, 60.3, 59.9, 56.2, 55.7, 20.2; MS
m/e630 (Mþ-2CO),602(Mþ - 3CO), 518 (Mþ - 6CO), 400 (Mþ -
Co2(CO)6); HRMS for C28H24Co2O13 (Mþ - 2CO) calcd
629.9997, found 629.9995.
3.94 (s, 3H), 3.84 (s, 3H), 3.66 (d, J = 14.0, 1H), 3.39 (s, 3H); 13
C
NMR 198.9 (br), 153.1, 152.7, 142.5, 137.7, 137.5, 132.6, 132.4,
132.0, 127.8, 126.4, 126.2, 107.9, 105.7, 92.9, 61.0, 60.4, 56.1,
40.0; MS m/e 538 (Mþ - 1CO), 510 (Mþ - 2CO), 482 (Mþ
-
3CO), 454 (Mþ - 4CO), 426 (Mþ - 5CO), 398 (Mþ - 6CO);
HRMS m/e for C24H16Co2O9 calcd 537.9509 (Mþ - CO), found
537.9492 .
Hexacarbonyl[μ-η4-(9-methoxy-2,4-dimethyl-5H-dibenzo[a,
c]cycloheptyne]dicobalt (9c). Subjecting acetate complex 8c
(0.1232 g, 0.207 mmol) to General Procedure C (6 h) gave 9c
(0.0938 g, 85% yield), following flash chromatography (50:1
petroleum ether/Et2O), as a brown solid: mp 142-144 °C; IR
Hexacarbonyl[μ-η4-(3-acetoxy-1-biphenyl-2-yl)-1-propy-
ne]dicobalt (8g). Subjecting 13g (0.0799 g, 0.384 mmol) to
General Procedure B gave acetate complex 8g (0.1763 g,
86% yield) following flash chromatography (50:1 petro-
leum ether/Et2O), as a red-brown oil which gradually
(KBr) νmax 2924, 2090, 2055, 2025 cm-1 1 H NMR (-30 °C) δ
;
7.54 (d, J=8.5, 1H), 7.21 (d, J = 3.0, 1H), 6.97 - 7.01 (m, 3H),
4.49 (d, J = 14.0, 1H), 3.93 (s, 3H), 3.34 (d, J = 14.0, 1H), 2.50
(s, 3H), 2.29 (s, 3H) ; 13C NMR 199.1, 159.4, 140.6, 139.0,
136.20, 136.15, 134.1, 132.2, 132.0, 131.7, 130.0, 116.7, 113.5,
solidified: mp 99-101 °C; IR (KBr) νmax 3073, 2977, 2087,
2055, 2006, 1749 cm-1
;
H NMR δ 7.77 (d, J = 7.8, 1H),
1
7.45-7.52 (m, 3H), 7.42 (apparent t, Jave = 7.6, 1H), 7.34
(apparent t, Jave=7.3, 1H), 7.26-7.30 (m, 2H), 7.14 (d, J=
7.8, 1H), 4.02 (s, 2H), 2.02 (s, 3H); 13C NMR 199.3, 170.4,
142.2, 141.2, 135.3, 134.3, 130.2, 129.3, 128.6, 128.3, 128.0,
127.6, 93.1, 88.4, 64.1, 20.3; MS m/e 480 (Mþ - 2CO), 452
(Mþ - 3CO), 396 (Mþ - 5CO), 368 (Mþ - 6CO). Anal. Calcd for
105.2, 92.7, 55.4, 32.9, 21.0, 20.9; MS m/e 534 (Mþ), 450 (Mþ
-
3CO), 394 (Mþ - 5CO); HRMS m/e for C24H16Co2O7 calcd
533.9560 (Mþ), found 533.9569.
Hexacarbonyl[μ-η4-(8-methoxy-4H-benzo[3,4]cycloheptyne-
[1,2-b]thiophene]dicobalt (9d) and Hexacarbonyl[μ-η4-(8-meth-
oxy-4H-benzo[3,4]cycloheptyne[1,2-c]thiophene]dicobalt (9d0).
Subjecting 8d (0.0654 g, 0.114 mmol) to General Procedure C
(5 h) afforded 9d/9d0 (0.0494 g, 82% yield) following flash
chromatography, as an inseparable 45:55 mixture, as a red-
C
23H14Co2O8 C, 51.52; H, 2.63. Found C, 51.75; H, 2.51.
Hexacarbonyl[μ-η4-(3-methoxy-(4-carbomethoxy-20,30,40-tri-
methoxybiphenyl-2-yl)-1-propyne)]dicobalt (8h). To a solution
of 16 (0.1223 g, 0.330 mmol) in CH2Cl2 at 0 °C was added
octacarbonyldicobalt (excess). The cooling bath was removed,
and the mixture was allowed to stir for 2 h. After concentration
under reduced pressure, flash chromatography (3:1 petroleum
ether/Et2O) afforded 8h (0.1797 g, 83% yield) as a red-brown
solid: mp 143-144 °C; IR (KBr) νmax 2956, 2091, 2039, 2009,
1726 cm-1; 1H NMR δ 8.45 (d, J=1.7, 1H), 7.93 (dd, J=7.9,
1.7, 1H), 7.18 (d, J=7.9, 1H), 6.80 (1/2 AB quartet, J=8.5, 1H),
6.74 (1/2 AB quartet, J=8.5, 1H), 3.97 (s, 3H), 3.96 (s, 3H), 3.94
(s, 3H), 3.87 (d, J = 13.4, 1H), 3.59 (s, 3H), 3.30 (s, 3H), 3.25 (d,
J=13.4, 1H); 13C NMR 199.4, 166.6, 154.0, 151.3, 142.4, 141.3,
137.8, 135.7, 131.2, 130.1, 128.1, 127.8, 124.9, 107.1, 95.7, 86.0,
71.7, 60.8, 60.6, 58.6, 56.3, 52.3; MS m/e 572 (Mþ - 3CO), 516
(Mþ - 5CO); HRMS for C27H22Co2O12 calcd (Mþ - 3CO)
571.9928, found 571.9924.
brown viscous oil: IR (KBr) νmax 2937, 2091, 2067, 2045, 1603 cm-1
.
1 H NMR: for 9d δ 7.53 (d, J=8.5, 1H), 7.24 (d, J=2.8, 1H), 7.18
(d, J=5.3, 1H), 7.13 (d, J=5.3, 1H), 6.95 (dd, J = 8.3, 2.8, 1H),
4.25 (s, 2H), 3.900 (s, 3H); for 9d0 δ 7.55 (d, J = 8.5, 1H), 7.28 (d,
J = 3.1, 1H), 7.19 (d, J = 2.8, 1H), 7.14 (obscured d, 1H), 6.93
(dd, J = 8.3, 2.8 1H), 4.17 (s, 2H), 3.897 (s, 3H); 13C NMR
199.0, 159.6, 159.1, 141.3, 139.5, 138.0, 137.2, 136.9, 135.7,
131.1, 130.2, 129.9, 127.1, 127.0, 125.4, 121.9, 121.5, 117.3,
117.1, 114.0, 113.8, 100.9, 100.4, 92.5, 55.4, 34.8, 33.3; MS m/e
512 (Mþ), 455 (Mþ - 2CO), 399 (Mþ - 4CO); HRMS m/e for
C20H10Co2O7S calcd 511.8811 (Mþ), found 511.8808.
Hexacarbonyl[μ-η4-(2,3,4,9-tetramethoxy-5H-dibenzo[a,c]cyclo-
heptyne]dicobalt (9e). Subjecting (8e) (0.6621 g, 1.01 mmol) to
General Procedure C (4.5 h) afforded 9e (0.5457 g, 91% yield)
following flash chromatography (7:1 petroleum ether/Et2O), as
a red-brown solid: mp 138-140 °C; IR (KBr) νmax 2938, 2091,
2051, 2023, 1601 cm-1; 1H NMR δ 7.47 (d, J = 8.7, 1H), 7.22 (d,
J = 2.7, 1H), 6.98 (dd, J = 8.7, 2.7, 1H), 6.67 (s, 1H), 4.03 (v br,
2H), 3.95 (s, 3H), 3.91 (s, 6H), 3.84 (s, 3H); 13C NMR 199.1,
159.5, 152.0, 150.1, 141.7, 138.9, 136.1, 131.35, 131.29, 127.1,
116.8, 113.6, 112.7, 105.6, 92.6, 61.4, 60.9, 56.2, 55.4, 29.4; MS
Hexacarbonyl[μ-η4-(1,2,3,9-tetramethoxy-5H-dibenzo[a,c]cyclo-
heptyne]dicobalt (9a). General Procedure C. To a solution of 8a
(0.1193 g, 0.182 mmol) in CH2Cl2 (35 mL) at 0 °C was added
diisopropylethylamine (48 μL, 1.5 equiv) and BF3-OEt2 (69 μL,
3.0 equiv). The cooling bath was removed, and the reaction was
allowed to stir for 6 h, at which time consumption of starting
material was complete. Following an extractive workup, flash
chromatography (5:1 petroleum ether/Et2O) afforded 9a
(0.0766 g, 71% yield), as a red-brown oil which gradually
solidified: mp 117-119 °C; IR (KBr) νmax 2939, 2090, 2020
cm-1; 1 H NMR δ 7.57 (d, J=8.5, 1H), 7.21 (d, J=3.0, 1H), 6.92
(dd, J=8.5, 2.5, 1H), 6.65 (s, 1H), 4.01 (d, J=14.0, 1H), 3.91 (s,
3H), 3.90 (s, 3H), 3.82 (s, 3H), 3.63 (d, J=14.0, 1H) 3.38 (s, 3H);
13C NMR 199.3, 198.7, 158.9, 152.9, 152.2, 142.3, 138.9, 137.2,
133.7, 126.1, 124.8, 116.5, 112.0, 107.7, 105.4, 93.0, 60.9, 60.2,
56.0, 55.1, 39.8; MS m/e 596 (Mþ), 540 (Mþ - 2CO), 512 (Mþ -
3CO), 484 (Mþ - 4CO); HRMS m/e for C25H18Co2O10 calcd
539.9666 (Mþ - 2CO), found 539.9642.
m/e 596 (Mþ), 568 (Mþ - CO), 540 (Mþ - 2CO), 512 (Mþ
-
3CO), 484 (Mþ - 4CO), 456 (Mþ - 5CO); HRMS for
C25H18Co2O10 (Mþ) calcd 595.9564, found 595.9548.
Hexacarbonyl[μ-η4-(1,2,3,8,9-pentamethoxy-5H-dibenzo[a,c]cyclo-
heptyne]dicobalt (9f). Subjecting (8f) (0.9250 g, 1.35 mmol) to
General Procedure C (4.5 h) afforded 9f (0.7021 g, 83% yield)
following flash chromatography (5:1 hexanes/Et2O), as a dark
brown solid: mp 115-117 °C; IR (KBr) νmax 2939, 2090, 2054,
1593 cm-1; 1H NMR δ 7.30 (d, J = 8.7, 1H), 6.97 (d, J = 8.7,
1H), 6.63 (s, 1H), 3.99 (d, J = 14.0, 1H), 3.99 (s, 3H), 3.95 (s,
3H), 3.92 (s, 3H), 3.81 (s, 3H), 3.67 (d, J = 14.0, 1H), 3.40 (s,
3H); 13C NMR 199.5, 153.1, 152.3, 152.0, 148.4, 142.3, 137.3,
132.2, 128.3, 126.3, 125.9, 110.6, 107.5, 107.3, 85.8, 61.0, 60.7,
Hexacarbonyl[μ-η4-(1,2,3-Trimethoxy-5H-dibenzo[a,c]cyclo-
heptyne]dicobalt (9b). Subjecting acetate complex 8b (0.0848 g,
8248 J. Org. Chem. Vol. 75, No. 23, 2010

Djurdjevic et al.
JOCArticle
60.4, 56.1, 55.8, 40.3; MS m/e 626 (Mþ), 598 (Mþ - CO), 570
1573 cm-1; 1H NMR δ 7.55 (d, J = 8.7, 1H), 6.94 (d, J = 8.7,
1H), 6.78 (d, J = 10.1, 1H), 6.58 (s, 1H), 6.29 (m, 1H), 3.95 (s,
3H), 3.91 (s, 3H), 3.90 (s, 3H), 3.85 (s, 3H), 3.48 (s, 3H), 3.06 (dd,
J = 12.9, 7.9, 1H), 2.80 (ddd, J = 12.9, 5.9, 1.8, 1H); 13C NMR
152.3, 150.4, 145.2, 140.7, 140.1, 132.2, 131.1, 128.3, 127.5,
124.0, 123.8, 109.9, 105.6, 61.0, 60.6, 60.4, 55.9, 55.8, 33.5; MS
m/e 342 (Mþ); HRMS for C20H22O5 calcd 342.1467, found
342.1475.
(Mþ - 2CO), 542 (Mþ - 3CO), 514 (Mþ - 4CO), 486 (Mþ
-
5CO), 458 (Mþ - 6CO); HRMS for C26H20Co2O11 (Mþ) calcd
625.9670, found 625.9673.
Hexacarbonyl[μ-η4-(5H-dibenzo[a,c]cycloheptyne]dicobalt (9g).
Subjecting 8g (0.0604 g, 0.127 mmol) to General Procedure C
(16 h) afforded 9g (0.0311, 58% yield) following flash chromatog-
raphy (100% petroleum ether), as a dark brown solid: mp
130-132 °C; IR (KBr) νmax 3059, 2959, 1688, 2091, 2052,
9-Carbomethoxy-1,2,3-trimethoxy-5H-dibenzo[a,c]cycloheptene
(17h). To a solution of 9h (0.1831 g, 0.293 mmol) in degassed 1,
2-dichloroethane (7 mL) was added bis(trimethylsilyl)acetylene
(0.14mL, 0.59mmol) andtriethylsilane(0.23mL, 0.14mmol). The
mixture was heated to 65 °C for 6 h and cooled to room
temperature, at which point trifluoroacetic acid (3.0 mL) was
added. After stirring for an additional 12 h, the mixture was
subjected to a conventional extractive workup. Preparative TLC
(5:1 hexanes/Et2O) afforded 17h (0.0789 g, 79% yield) as a
colorless solid: mp 85-86 °C; IR (KBr) νmax 2950, 1722, 1594
cm-1; 1H NMR δ 8.03 (s, 1H), 7.91 (1/2 AB quartet, J = 8.3, 1H),
7.89 (1/2 AB quartet, J = 8.3, 1H), 6.62 (d, J = 10.0, 1H), 6.59 (s,
1H), 6.29 (m, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.90 (s, 3H), 3.46 (s,
3H), 3.08 (m, 1H), 2.75 (m, 1H); 13C NMR 167.0, 153.3, 152.3,
140.8, 140.5, 139.4, 136.5, 133.2, 132.0, 130.1, 128.8, 127.6, 125.4,
123.3, 105.8, 61.1, 60.7, 55.9, 52.1, 33.3; MS m/e 340 (Mþ); HRMS
for C20H20O5 (Mþ) calcd 340.1311, found 340.1306.
6,7-Dihydro-3,9,10,11-tetramethoxy-5H-dibenzo[a,c]cyclohepten-
5-one (18a). To a solution of alkene 17a (0.0521 g, 0.167 mmol) in
THF (7 mL) at 0 °C was added BH3-THF (0.75 mL of a 1 M
solution). The cooling bath was removed, and the reaction was
stirred at room temperature for 12 h. NaOH (1 mL of a 10%
aqueous solution) and H2O2 (1 mL of a 33% aqueous solution)
were added, and the mixture was stirred for 4 h, followed by
warming to 40 °C for 0.5 h. A conventional workup gave a crude
alcohol which was added slowly as a solution in CH2Cl2 to a -78 °C
solution prepared from the addition of DMSO (0.14 mL, 2.0
mmol) to oxalyl chloride (86 μL, 1.0 mmol) in CH2Cl2 (10 mL)
at -78 °C. Diisopropylethylamine (0.70 mL, 4.0 mmol) was
added, and the solution was allowed to come to room temperature
over 6 h. A conventional workup gave a residue with a 96:4
mixture of ketone regioisomers (by integration of relevant 1H
NMR resonances); preparative TLC (1:1 hexanes/Et2O) afford
18a (0.0440, 80% yield) as a colorless solid: mp 141-2 °C
(hexanes), lit. 142-3 °C (MeOH),5a 140.5-141 °C,30 135-6 °C.11
6,7-Dihydro-3,8,9,10-tetramethoxy-5H-dibenzo[a,c]cyclohepten-
5-one. (18e). To a solution of alkene 17e (0.1793 g, 0.574 mmol) in
THF (20 mL) at 0 °C was added BH3-THF (2.7 mL of a 1 M
solution). The cooling bath was removed, and the reaction was
stirred at room temperature for 12 h. NaOH (3 mL of a 10%
aqueous solution) and H2O2 (3 mL of a 33% aqueous solution)
were added, and the mixture was stirred for 4 h, followed by
warming to 40 °C for 0.5 h. A conventional workup gave a crude
alcohol which was dissolved in CH2Cl2 (20 mL). To this solution
was added PDC (0.55 g), and the mixture was stirred for 12 h. A
conventional workup followed by preparative TLC (3:1 petroleum
ether/Et2O) afforded 18e (0.1291 g, 68% yield) as a colorless solid:
mp 123-125 °C; IR (KBr) νmax 2937, 1681, 1601 cm-1; 1H NMR
δ 7.36 (m, 1H), 7.14 (s, 1H), 7.13 (obscured m, 1H), 6.69 (s, 1H),
3.92 (s, 3H), 3.89 (s, 3H), 3.88 (s, 6H), 2.97-3.00 (m, 2H),
2.92-2.94 (m, 2H); 13C NMR 206.3, 158.9, 152.2, 150.1, 141.6,
139.7, 134.4, 131.4, 130.5, 125.4, 118.8, 112.1, 109.0, 61.3, 60.8,
56.0, 55.4, 47.3, 20.4; MS m/e 328 (Mþ); HRMS for C19H20O5
(Mþ) calcd 328.1311, found 328.1322.
1
2022 cm-1
;
H NMR δ 7.71 (m, 1H), 7.59 (s, 1H), 7.40-7.47
(m, 3H), 7.28-7.36 (m, 3H), 4.05 (s, 2H); 13C NMR 199.0, 140.4,
140.2, 138.5, 137.3, 133.2, 132.1, 130.4, 128.6, 128.3, 127.92,
127.86, 127.5, 104.2, 92.0, 39.9; MS m/e 420 (Mþ - 2CO), 336
(Mþ - 5CO), 308 (Mþ - 6CO); HRMS m/e for C21H10Co2O6
calcd 447.9192 (Mþ - CO), found 447.9214.
Hexacarbonyl[μ-η4-(9-carbomethoxy-1,2,3-trimethoxy-5H-
dibenzo[a,c]cycloheptyne]dicobalt (9h). Subjecting (8h) (0.2304
g, 0.351 mmol) to General Procedure C (5 h) afforded 9h
(0.1831 g, 84% yield) following flash chromatography (5:1
petroleum ether/Et2O), as a dark brown viscous oil: IR (KBr)
ν
max 2952, 2092, 2055, 2023, 1730 cm-1; 1H NMR δ 8.30 (d, J=
1.9, 1H), 7.98 (dd, J = 8.2, 1.9, 1H), 7.69 (d, J = 8.2, 1H), 6.67
(s, 1H), 4.05 (d, J = 14.1, 1H), 3.98 (s, 3H), 3.95 (s, 3H), 3.84 (s,
3H), 3.65 (d, J = 14.1, 1H), 3.39 (s, 3H); 13C NMR 198.7,
166.7, 153.24, 153.15, 142.4, 138.3, 137.9, 137.0, 132.9, 129.4,
126.8, 125.5, 107.9, 105.4, 91.4, 61.1, 60.6, 56.1, 52.3, 39.9; MS
m/e 596 (Mþ-1CO), 568 (Mþ-2CO), 540 (Mþ - 3CO), 512
(Mþ-4CO), 484 (Mþ-5CO);); HRMS for C26H18Co2O11
(Mþ - 3CO) calcd 539.9666, found 539.9683.
1,2,3,9-Tetramethoxy-5H-dibenzo[a,c]cycloheptene (17a). To
a solution of 9a (0.0782 g, 0.131 mmol) in degassed 1,2-dichlo-
roethane (2 mL) was added bis(trimethylsilyl)acetylene (62 μL,
0.274 mmol) and triethylsilane (0.10 mL, 0.63 mmol). The
mixture was heated to 65 °C for 6 h and cooled to room
temperature, at which point trifluoroacetic acid (0.5 mL) was
added. After stirring for an additional 12 h, the mixture was
subjected to a conventional extractive workup. Preparative TLC
(4:1 hexanes/Et2O) afforded 17a (0.0396 g, 97% yield) as a
colorless solid: mp 102-3 °C (MeOH), lit.29 102-3 °C (MeOH).
2,3,4,9-Tetramethoxy-5H-dibenzo[a,c]cycloheptene (17e). To
a solution of 9e (0.3492 g, 0.586 mmol) in degassed 1,2-dichlo-
roethane (20 mL) were added bis(trimethylsilyl)acetylene (0.27
mL, 1.2 mmol) and triethylsilane (0.47 mL, 2.9 mmol). The
mixture was heated to 65 °C for 6 h and cooled to room
temperature, at which point trifluoroacetic acid (1.0 mL) was
added. After stirring for an additional 12 h, the mixture was
subjected to a conventional extractive workup. Preparative TLC
(10:1 petroleum ether/Et2O) afforded 17e (0.1718 g, 94% yield)
1
as a colorless viscous oil: IR (KBr) νmax 2936, 1604 cm-1; H
NMR δ 7.61 (d, J = 8.7, 1H), 6.95 (dd, J = 8.7, 2.6, 1H), 6.85 (d,
J = 2.6, 1H), 6.82 (s, 1H), 6.57 (d, J = 10.0, 1H), 6.26 (m, 1H),
3.94 (s, 3H), 3.93 (s, 3H), 3.90 (s, 3H), 3.89 (s, 3H), 2.47 (v br,
2H); 13C NMR 158.2, 151.1, 148.9, 141.9, 137.4, 134.3, 132.8,
132.3, 130.7, 129.6, 128.3, 113.4, 112.9, 109.1, 61.5, 60.9, 56.2,
55.3, 24.0; MS m/e 312 (Mþ); HRMS for C19H20O4 (Mþ) calcd
312.1362, found 312.1356.
1,2,3,8,9-Pentamethoxy-5H-dibenzo[a,c]cycloheptene (17f).
To a solution of 9f (0.0945 g, 0.151 mmol) in degassed 1,2-
dichloroethane (2 mL) were added bis(trimethylsilyl)acetylene
(62 μL, 0.32 mmol) and triethylsilane (0.12 mL, 0.76 mmol). The
mixture was heated to 65 °C for 6 h and cooled to room
temperature, at which point trifluoroacetic acid (0.5 mL) was
added. After stirring for an additional 12 h, the mixture was
subjected to a conventional extractive workup. Preparative TLC
(7:1 petroleum ether/Et2O) afforded 17f (0.0465 g, 90% yield) as
a colorless solid: mp 163-165 °C; IR (KBr) νmax 3036, 2926,
6,7-Dihydro-3,4,9,10,11-pentamethoxy-5H-dibenzo[a,c]cyclohepten-
5-one (18f). To a solution of alkene 17f (0.2175 g, 0.636 mmol) in
THF (25 mL) at 0 °C was added BH3-THF (3.0 mL of a 1 M
(30) Rapoport, H.; Williams, A. R.; Cisney, M. E. J. Am. Chem. Soc.
1950, 72, 3324–3325.
(29) Boye, O.; Itoh, Y.; Brossi, A. Helv. Chim. Acta 1989, 72, 1690–1696.
J. Org. Chem. Vol. 75, No. 23, 2010 8249

Djurdjevic et al.
JOCArticle
solution). The cooling bath was removed, and the reaction was
stirred at room temperature for 12 h. NaOH (3 mL of a 10%
aqueous solution) and H2O2 (3 mL of a 33% aqueous solution)
were added, and the mixture was stirred for 4 h, followed by
warming to 40 °C for 0.5 h. A conventional workup gave a crude
alcohol which was dissolved in CH2Cl2 (20 mL). To this solution
was added PDC (0.55 g), and the mixture was stirred for 12 h. A
conventional workup followed by preparative TLC (3:1 petroleum
ether/Et2O) afforded 18f (0.1505 g, 67% yield) as a colorless solid:
mp 164-165 °C, lit. 156-157 °C;22 IR (KBr) νmax 2939, 1701,
1598 cm-1; 1H NMR δ 7.26 (d, J = 8.6, 1H), 7.00 (d, J = 8.6, 1H),
6.56 (s, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.86 (s, 6H), 3.57 (s, 3H),
2.97-3.05 (m, 2H), 2.85 (m, 1H), 2.59 (m, 1H); 13C NMR 204.8,
152.6, 151.8, 151.7, 144.3, 141.4, 135.24, 135.21, 126.24, 126.16,
123.8, 113.0, 107.5, 62.2, 61.0, 60.8, 55.9, 55.8, 49.6, 30.1; MS m/e
354 (Mþ); HRMS for C20H22O6 (Mþ) calcd 358.1416, found
358.1402.
6,7-Dihydro-3-carbomethoxy-9,10,11-trimethoxy-5H-dibenzo[a,
c]cyclohepten-5-one (18h). To a solution of alkene 17h (0.0307 g,
0.0902 mmol) in THF (5 mL) at 0 °C was added BH3-THF (0.45
mL of a 1 M solution). The cooling bath was removed, and the
reaction was stirred at room temperature for 12 h. NaOH (1 mL of
a 10% aqueous solution) and H2O2 (1 mL of a 33% aqueous
solution) were added, and the mixture was stirred for 4 h, followed
by warming to 40 °C for 0.5 h. A conventional workup gave a
crude alcohol which was dissolved in CH2Cl2 (10 mL). To this
solution was added PDC (0.5 g), and the mixture was stirred for
12 h. A conventional workup followed by preparative TLC (1:1
petroleum ether/Et2O) afforded 18h (0.0.0260 g, 81% yield) as a
colorless solid: mp 144-145 °C; lit.6 144.2-144.8 °C.
159.4, 151.7, 150.8, 143.2, 141.3, 135.4, 130.3, 129.0, 125.0, 112.5,
108.7 (br), 107.9, 70.7 (br), 61.6, 61.0, 55.1, 55.4, 41.5, 21.5; MS m/e
330 (Mþ); HRMS for C19H22O5 (Mþ) calcd 330.1467, found
330.1481.
(5S)-5-Azido-6,7-dihydro-3,9,10,11-tetramethoxy-5H-dibenzo[a,
c]cycloheptene (20a). To a suspension of alcohol 19a (0.0583 g,
0.176 mmol), Zn(N3)2-(pyridine)2 (0.0810 g, 0.264 mmol), and
triphenylphosphine (0.185 g, 0.704 mmol) in toluene (2 mL) was
added diisopropyl azodicarboxylate (0.14 mL, 0.70 mmol) in a
dropwise fashion. After stirring for 4 h, the mixture was filtered
through a plug of silica gel, and concentrated under reduced
pressure. Preparative TLC (4:1 hexanes/Et2O) afforded 20a con-
taminated by 10% of alkene 17a (0.0440 g, 64% of 20a, 7% of
17a). Repeated preparative TLC (10:1 hexanes/EtOAc) afforded
pure 20a as a viscous oil, [R]22D 110° (c 0.0100) (93% ee material as
evaluated on 2); IR(KBr) νmax 2936, 2013 cm-1; 1 H NMR (major
atropisomer, 91%) δ 7.42 (d, J = 8.5, 1H), 7.13 (d, J = 2.5, 1H),
6.92 (dd, J = 8.5, 2.5, 1H), 6.60 (s, 1H), 4.44 (dd, J = 11.5, 7.0,
1H), 3.92 (s, 6H), 3.90 (s, 3H), 3.65 (s, 3H), 2.45-2.60 (m, 2H),
2.33 (m, 1H), 2.00 (m, 1H); resonances from the minor atropi-
somer (9%) could be observed at 7.42 (d, J = 8.8, 1H), 6.97 (dd,
J = 8.8, 2.6, 1H), 6.81 (d, J = 2.6, 1H), 6.58 (s, 1H), 4.71 (d, J =
6.8, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 3.62 (s, 3H); 13C NMR 159.0,
152.6, 150.9, 141.2, 138.6, 134.7, 131.7, 126.0, 124.3, 112.5, 109.2,
107.6, 61.1, 61.0, 60.8, 56.0, 55.3, 38.9, 30.4; MS m/e355 (Mþ);HRMS
m/e for C19H21N3O4 calcd 355.1532 (Mþ), found 355.1541.
(S)-N-Acetyl-O-methyl-colchicinol (NSC 51046) (2). To a
solution containing azide 20a with 10% alkene 17a (0.0186 g,
48.1 μmol 20a) in 100% EtOH saturated with H2 was added
Lindlar catalyst (0.0068 g). The mixture was stirred under H2 for
20 h, filtered through Celite, and concentrated under reduced
pressure. The residue was dissolved in CH2Cl2 and cooled to
0 °C, and acetic anhydride (0.2 mL) and pyridine (0.2 mL) were
added. The mixture was allowed to stir 12 h with gradual
warming to room temperature. Concentration under reduced
pressure, followed by preparative TLC (19:1 CH2Cl2/MeOH)
afforded 2 (0.0157 g, 88% yield), which was spectroscopically
identical with authentic material,5,11 93% ee (Chiralcel OD-H,
10% i-PrOH/hexanes). A single recrystallization afforded 2 of
>99% ee: mp 203-4 °C (CH2Cl2/hexanes); lit.4b 204-5 °C
(5R)-6,7-Dihydro-3,9,10,11-tetramethoxy-5H-dibenzo[a,c]cyclo-
hepten-5-ol (19a). A suspension of 3-nitrophenylboronic acid
(0.334 g, 2.0 mmol), L-tartaric acid (0.0300 g, 2.0 mmol), and
CaH2 (0.168 g, 4.0 mmol) in THF (5 mL) was heated to reflux for
1 h. After cooling and the solids were allowed to settle, the
supernatant solution (2.5 mL, ca. 1 mmol) was added to ketone
18a (0.0634 g, 0.193 mmol). Lithium borohydride (0.5 mLof a 2 M
solution, 1.0 mmol) was added over a period of 5 min, and the
solution was stirred for 0.5 h. NaOH (1 mL of a 10% aqueous
solution) and water (2 mL) were added, and the reaction subjected
to a conventional extractive workup. Preparative TLC (2:1 petro-
leum ether/Et2O) afforded 19a (0.0610 g, 96%), 95% ee (Chiralcel
(CH2Cl2/hexanes); [R]24D -64° (c 0.0056, CHCl3); lit.4b [R]20
-
H
D
65° (c 0.46, CHCl3); lit.4a [R]20D -64.9° (c 1.03%, CHCl3); 1
OD-H, i-PrOH/hexanes): mp 137-9 °C (CH2Cl2/petroleum
D
NMR (DMSO-d6) δ 8.34 (d, J = 8.6, 1H), 7.25 (d, J = 8.4, 1H),
6.91 (d, J = 2.6, 1H), 6.87 (dd, J = 8.4, 2.6, 1H), 6.76 (s, 1H),
4.52 (m, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.47 (s, 3H),
2.48 (m, 1H, obscured), 2.15 (m, 1H), 2.07 (m, 1H), 1.88 (s, 3H),
1.85 (m, 1H); 13C NMR (DMSO-d6) 168.2, 158.3, 152.1, 150.3,
141.8, 140.5, 134.7, 130.5, 126.1, 124.3, 110.7, 109.4, 108.1,
60.50, 60.45, 55.8, 54.9, 48.1, 30.1, 22.6.
1
ether) [R]22 120° (c 0.0144); H NMR (DMSO-d6) δ 7.24 (d,
J = 8.4, 1H), 7.17 (d, J = 2.8, 1H), 6.85 (dd, J = 84, 2.8, 1H), 6.75
(s, 1H), 5.23 (d, J = 4.7, 1H), 4.27 (m, 1H), 3.82 (s, 3H), 3.80 (s,
3H), 3.75 (s, 3H), 3.48 (s, 3H), 2.32-2.45 (m, 2H), 2.06 (m, 1H),
1.73 (m, 1H); 13C NMR (DMSO-d6) 158.3, 151.9, 150.2, 144.5,
140.4, 135.2, 130.3, 124.9, 124.0, 111.2, 108.7, 107.9, 68.1, 60.5,
60.4, 55.8, 54.9, 41.3, 29.9; HRMS m/e for C19H22O5 calcd
330.1467 (Mþ), found 330.1479.
(5S)-5-Azido-6,7-dihydro-3,8,9,10-tetramethoxy-5H-dibenzo-
[a,c]cycloheptene (20e). To a suspension of 19e (0.0346 g, 0.105
mmol), Zn(N3)2-(pyridine)2 (0.0484 g, 0.157 mmol), and triphe-
nylphosphine (0.1099 g, 0.419 mmol) in toluene (3 mL) was
added diisopropyl azodicarboxylate (81 μL, 0.42 mmol) in a
dropwise fashion. After stirring for 4 h, the mixture was filtered
through a plug of silica gel and concentrated under reduced
pressure. Preparative TLC (4:1 hexanes/EtOAc) afforded 20e
(5R)-6,7-Dihydro-3,8,9,10-tetramethoxy-5H-dibenzo[a,c]cyclo-
hepten-5-ol (19e). A suspension of 3-nitrophenylboronic acid (0.334
g, 2.0 mmol), L-tartaric acid (0.0300 g, 2.0 mmol), and CaH2 (0.168
g, 4.0 mmol) in THF (5 mL) was heated to reflux for 1 h. After
cooling and the solids were allowed to settle, the supernatant
solution (2.5 mL, ca. 1 mmol) was added to ketone 18e (0.0217 g,
0.0661 mmol). Lithium borohydride (0.2 mL of a 2 M solution, 0.4
mmol) was added over a period of 1.5h, and the solution stirred for
0.5 h. NaOH (1 mL of a 10% aqueous solution) and water (2 mL)
were added, and the reaction subjected to a conventional extrac-
tive workup. Preparative TLC (1:1 petroleum ether/Et2O) af-
forded 19e (0.0213 g, 98%), 98% ee (Chiralcel AS-H, 10% i-
(0.0286 g, 77% yield) as a viscous oil: [R]24 -126° (c 0.663,
D
CHCl3) (95% ee material as evaluated on 21); IR (KBr) νmax
2937, 2095 cm-1; 1H NMR δ 7.31 (d, J = 8.4, 1H), 7.12 (br s,
1H), 6.94 (dd, J = 8.4, 2.7, 1H), 6.70 (s, 1H), 4.46 (m, 1H), 3.94
(s, 3H), 3.91 (s, 3H), 3.905 (s, 3H), 3.900 (s, 3H), 3.01 (br m, 1H),
2.55 (m, 1H), 2.06 (m, 2H); 13C NMR (DMSO-d6) 158.8, 151.6,
150.3, 141.0, 138.0, 134.7, 130.7, 129.9, 123.4, 112.8, 110.6 (br),
108.2, 61.4, 61.2, 60.4, 55.8, 55.2, 38.1, 21.3; MS m/e 355 (Mþ);
HRMS for C19H21N3O4 (Mþ) calcd 355.1532, found 355.1537.
(5S)-5-Acetamido-6,7-dihydro-3,8,9,10-tetramethoxy-5H-dibenzo-
[a,c]cycloheptene (21). To a solution containing azide 20e with
PrOH/hexanes) as a viscous oil, [R]22 102° (c 0.533); IR (KBr)
D
max 3500 br, 2936, 1646 cm-1; 1H NMR (DMSO-d6) 7.30 (d, J =
ν
8.5, 1H), 7.18 (d, J = 2.5, 1H), 6.91 (dd, J = 8.5, 2.5, 1H), 5.25 (d,
J = 4.5, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H),
2.86 (m, 1H), 2.38 (m, 3H), 1.75-1.86 (m, 2H); 13CNMR(CDCl3)
8250 J. Org. Chem. Vol. 75, No. 23, 2010

Djurdjevic et al.
JOCArticle
(0.0286 g, 80.5 μmol) in 100% EtOH (10 mL) saturated with H2
was added Lindlar catalyst (0.0109 g). The mixture was stirred
under H2 for 20 h, filtered through Celite, and concentrated under
reduced pressure. The residue was dissolved in CH2Cl2 (10 mL)
and cooled to 0 °C, and acetic anhydride (0.2 mL) and pyridine (0.2
mL) were added. The mixture was allowed to stir for 12 h with
gradual warming to room temperature. Concentration under
reduced pressure, followed by preparative TLC (19:1 CH2Cl2/
MeOH) afforded 21 (0.0237 g, 79% yield) in 95% ee (Chiralcel
OD-H, 10% i-PrOH/hexanes). A single recrystallization afforded
21 of >99% ee, as colorless crystals: mp 186-188 °C (Et2O/
hexanes); [R]22D -52.4° (c 0.783, CHCl3); IR (KBr) νmax 3288 br,
2936, 1664 cm-1; 1H NMR (DMSO-d6) 8.41 (d, J = 8.4, 1H), 7.32
(d, J = 8.1, 1H), 6.88-6.94 (m, 2H), 6.79 (s, 1H), 4.51 (m, 1H),
3.85 (s, 3H), 3.79 (s, 6H), 3.78 (s, 3H), 2.91 (dd, J = 13.2, 6.0, 1H),
2.16 (m, 1H), 1.95 (m, 1H), 1.89 (s, 3H), 1.78 (m, 1H); 13C NMR
(DMSO-d6) 168.6, 158.9, 151.6, 150.4, 141.4, 140.9, 135.3, 130.9,
129.3, 123.7, 111.3, 110.1, 108.3, 61.5, 60.4, 55.9, 55.1, 48.4, 22.7,
21.9; (a resonance at 40.0 in CDCl3 is obscured in DMSO-d6); MS
m/e 371 (Mþ); HRMS for C21H25NO5 (Mþ) calcd 371.1733,
found 371.1740.
Acknowledgment. The authors are grateful to NSERC
(Canada), the Canada Foundation for Innovation (CFI),
and the Ontario Innovation Trust (OIT) for support of this
research.
1
Supporting Information Available: H and 13C spectra for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 23, 2010 8251