Diels-Alder approach to tetra-ortho-substituted biaryls employing propargylic tertiary alcohols as dienophiles

Article abstract of DOI:10.1021/jo070812e

(Chemical Equation Presented) The efficient synthesis of a series of tetra-ortho-substituted biaryls is described utilizing a Diels-Alder reaction between propargylic tertiary alcohols and cyclic oxygenated dienes. The successful resolution of one of the

Full text of DOI:10.1021/jo070812e

TABLE 1. Synthesis of Propargyl Alcohols
Diels-Alder Approach to Tetra-ortho-Substituted
Biaryls Employing Propargylic Tertiary Alcohols
as Dienophiles
Bradley O. Ashburn and Rich G. Carter*
Department of Chemistry, Oregon State UniVersity,
153 Gilbert Hall, CorVallis, Oregon 97331
entry
ketone
yield
a
b
c
d
e
f
acetone
3-pentanone
cyclobutanone
cyclopentanone
cyclohexanone
benzophenone
4,4′-dimethylbenzophenone
4,4-dichlorobenzophenone
71% (R ) Me)
rich.carter@oregonstate.edu
63% (R ) Et)
60% (R ) (CH2)3)
52% (R ) (CH3)4)
68% (R ) (CH2)5)
77% (R ) Ph)
78% (R ) p-Me-C6H4)
69% (R ) p-Cl--C6H4)
ReceiVed April 17, 2007
g
h
i
9-fluorenone
77%
THF, -78 °C followed by the addition of the electrophile,
-78 °C to rt) generated the propargylic alcohols in moderate
to good yield (52-78%). Both acyclic and cyclic ketones with
either alkyl or aromatic substituents were tolerated in this
transformation. It should be noted that attempts at formation of
the secondary alcohol derived from trapping the lithiated
acetylene with benzaldehyde led to extensive decompositions
possibly due to Oppenhauer-type4 hydride transfer by the
resultant propargylic secondary alkoxide.
The efficient synthesis of a series of tetra-ortho-substituted
biaryls is described utilizing a Diels-Alder reaction between
propargylic tertiary alcohols and cyclic oxygenated dienes.
The successful resolution of one of the biaryls is achieved
through derivatization with menthyl chloroformate followed
by crystallization. The menthyl carbamate is cleaved under
basic conditions to reveal enantiomerically pure biaryl
compounds.
With the alkynes in hand, we turned our attention to the key
Diels-Alder cycloaddition (Table 2). We were gratified to find
that treatment of the propargyl alcohols 2 with the commercially
Diels-Alder cycloaddition has been shown to be an effective
method for the formation of sterically challenging carbon-
carbon bonds.1 Our laboratory2 and others3 have exploited this
unique reactivity for the construction of biaryl compounds. This
Diels-Alder approach to biaryls (DAB) has allowed us to
construct biaryl compounds possessing four different substituents
at the four ortho positions2a,csa feat that has not been previously
reported. Our previous cases have focused on the cycloaddition
of disubstituted alkynes with oxygenated, cyclic, and acyclic
dienes to yield (after aromatization) the required tetra-ortho-
substituted biaryls. In each case, both substituents on the alkyne
were able to activate the dienophile via their resonance-based,
electron-withdrawing character. In this Note, we describe for
the first time the ability to construct tetra-ortho-substituted biaryl
compounds using alkynes possessing just one resonance-based,
electron-withdrawing group.
(3) Prior examples of using a Diels-Alder reaction to construct a
biaryl: (a) Reed, J. A.; Schilling, C. L.; Tarvin, R. F.; Rettig, T. A.; Stille,
J. K. J. Org. Chem. 1969, 34, 2188-92. (b) McDonald, E.; Suksamrarn,
A.; Wylie, R. D. J. Chem. Soc., Perkin Trans. 1 1979, 1893-900. (c)
Weinreb, S. M.; Basha, F. Z.; Hibino, S.; Khatri, N. A.; Kim, D.; Pye, W.
E.; Wu, T.-T. J. Am. Chem. Soc. 1982, 104, 536-44. (d) Boger, D. L.;
Panek, J. S.; Duff, S. R. J. Am. Chem. Soc. 1985, 107, 5745-54. (e)
Effenberger, F.; Ziegler, T. Chem. Ber. 1987, 120, 1339-46. (f) Kanakam,
C. C.; Mani, N. S.; Ramanathan, H.; Subba Rao, G. S. R. J. Chem. Soc..
Perkin Trans. 1 1989, 1907-13. (g) Sain, B.; Sandhu, J. S. J. Org. Chem.
1990, 55, 2545-46. (h) Bateson, J. H.; Smith, C. F.; Wilkinson, J. B. J.
Chem. Soc., Perkin Trans 1 1991, 651-53. (i) Smith, D. M.; Royles, B. J.
L. J. Chem. Soc., Perkin Trans. 1 1994, 355-58. (j) D’Auria, M.
Tetrahedron Lett. 1995, 36, 6567-70. (k) Knolker, H.-J.; Baum, E.;
Hopfmann, T. Tetrahedron Lett. 1995, 36, 5339-42. (l) Avenoza, A.; Busto,
J. H.; Cativiela, C.; Peregrina, J. M. Synthesis 1995, 671-74. (m) Bala´zs,
L.; Ka´das, I.; To˜ke, L. Tetrahedron Lett. 2000, 41, 7583-87. (n) Watson,
M. D.; Fechtenkotter, A.; Mullen, K. Chem. ReV. 2001, 101, 1267-300.
(o) Min, S.-H.; Kim, Y.-W.; Choi, S.; Park, K. B.; Cho, C.-G. Bull. Korean
Chem. Soc. 2002, 23, 1021-22. (p) Hilt, G.; Smolko, K. I. Synthesis 2002,
686-92. (q) Hilt, G.; Smolko, K. I.; Lotsch, B. V. Synlett 2002, 1081-84.
(r) Moore, J. E.; York, M.; Harrity, J. P. A. Synlett 2005, 860-62. (s)
Yamato, T.; Miyamoto, M.; Hironaka, T.; Miura, Y. Org. Lett. 2005, 7,
3-6. (t) Hilt, G.; Galbiati, F.; Harms, K. Synthesis 2006, 3575-84. (u)
Liu, Y.; Lu, K.; Dai, M.; Wang, K.; Wu, W.; Chen, J.; Quan, J.; Yang, Z.
Org. Lett. 2007, 9, 805-08.
The synthesis of the propargylic tertiary alcohols is shown
in Table 1. Starting from the known alkyne 1 (available in one
step2b from the commercially available 2-chloro-6-nitrobenzal-
dehyde), deprotonation with our standard conditions (LDA,
(1) (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998,
37, 388-401. (b) Trost, B. M.; Jiang, C. Synthesis 2006, 369-96.
(2) (a) Ashburn, B. O.; Carter, R. G. Angew. Chem., Int. Ed. 2006, 45,
6737-41. (b) Naffziger, M. R.; Ashburn, B. O.; Perkins, J. R.; Carter R.
G. J. Org. Chem. 2007, 129, 9109-9116. (c) Ashburn, B. O.; Carter, R.
G.; Zakharov, L. N. J. Am. Chem. Soc. 2007, 72, 9857-9865.
(4) (a) Auge´, J.; Lubin-Germain, N.; Seghrouchni, L. Tetrahedron Lett.
2003, 44, 819-21. For reviews on Oppenauer oxidations, see: (b) de
Graauw, C. F.; Peters, J. A.; Huskens, B. J. Synthesis 1994, 1007-17. (c)
Djerassi, C. Org. React. 1951, 6, 207-72.
10.1021/jo070812e CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/29/2007
10220
J. Org. Chem. 2007, 72, 10220-10223

TABLE 2. Diels-Alder Construction of Biaryls
SCHEME 1. Diene Scope in Diels-Alder Construction of
Biaryls
entry
alkyne
yield
a
b
c
d
e
f
2a
2b
2c
2d
2e
2f
72% (R ) Me)
58% (R ) Et)
67% (R ) (CH2)3)
55% (R ) (CH3)4)
62% (R ) (CH2)5)
80% (R ) Ph)
79% (R ) p-Me-C6H4)
67% (R ) p-Cl-C6H4)
g
h
2g
2h
i
2i
68%
available 1-methoxy-1,3-cyclohexadiene (3) in xylenes at
145 °C cleanly generated the tetra-ortho-substituted biaryls 4.
The yields for this transformation were generally high (55-
80%). Of note is the fact that the significant steric requirement
for the construction of the tetra-ortho-substituted biaryl with a
tertiary alcohol moiety is nicely addressed through this DAB
strategy. The regiochemistry from the Diels-Alder process was
confirmed for each product by HMBC analysis. These reactions
are believed to proceed through a bicyclic intermediate followed
by the extrusion of ethylene to generate the biaryl 4. If the
reaction is conducted initially at a lower temperature (e.g.,
100 °C, 25 h), the intermediate bicycle can be observed via
NMR analysis of the crude mixture. One possible explanation
for the facile nature of these transformations could be internal
hydrogen bond activation between the propargylic alcohol and
either the nitro or chloro moieties. Support for this working
hypothesis can be found in the inability of the TMS silylated
alcohol (TMSCl, imidazole, cat. DMAP, CH2Cl2, 65%, 88%
borsm) version of 2f to undergo the same cycloaddition (130-
150 °C over 43 h).
We also explored the degree of diene variation that was
tolerated under the reaction process (Scheme 1). We initially
screened our standard acyclic dienes2 (Brassard’s diene5 and
commercially available TBS Danishefsky’s diene6); however,
we found that they were not amenable to the cycloaddition
process. We have previously observed a similar behavior for
our carbonyl-containing alkyne series.2c A range of cyclic dienes
did successfully undergo the Diels-Alder reaction and gave
rise to highly functionalized biaryls. We were pleased to find
that an o-amino functionality could be incorporated via the
previously unknown diene 6 (synthesized from 1,3-cyclohex-
anedione in three steps) in reasonable yield. Dioxygenated dienes
87 and 102b also cleanly yielded their requisite biaryl products
9 and 11 in excellent yields (95% and 72%, respectively).
One important attribute of highly substituted biaryls is the
restricted rotation around the σ aryl-aryl linkage. Consequently,
enantiomerically enriched biaryls have proven useful as chiral
ligands in a range of enantioselective pathways.8 We have
developed an efficient protocol to obtain enantiomerically
enriched biaryls from our DAB process (Scheme 2). Biaryl 4f
was chosen as a representative example. After reduction of 4f
with zinc in acetic acid (94%), the resultant aniline moiety
was treated with commercially available (-)-menthyl chloro-
formate 13 (Scheme 2). After standard column chromatography,
the diastereomeric carbamates were dissolved in hexanes. We
were pleased to observe crystallization of a single diastereomer
14-(aR) from the mother liquor in excellent yield and diaste-
reoselectivity (45%, >20:1 dr). Confirmation of the absolute
stereochemistry was obtained by X-ray crystallographic analy-
sis of biaryl 14-(aR). Concentration of the mother liquor and a
second recrystallization from hexanes revealed that the re-
maining material consisted of the alternate diastereomer 14-
(aS)sagain in excellent yield and diastereoselectivity
(44%, >20:1 dr).
Cleavage of the carbamate was possible under basic condi-
tions (Scheme 3). Treatment of diastereomer 14-(aR) with KOH
in hot n-butanol/triethyleneglycol provided a 79% yield of the
amino alcohol 15-(aR). Confirmation that no racemization had
occurred under the reaction conditions was achieved by reacy-
lation of 15-(aR) with (-)-menthyl chloroformate (13) to
provide 14-(aR) as a single diastereomer (86%). Attempted
cleavage of the diastereomeric carbamate 14-(aS) gave the
desired product 15-(aS) in only modest yield (32%). A second
product 16 was competitively produced under the reaction
conditions (57%). Extended reaction time led to exclusive
formation of this dibenzo[b,d]pyran 16 in 92% yield. This
product 16 is presumably formed via nucleophilic aromatic
substitution by the tertiary alcohol on the aryl chloride. It is
worth noting that this compound is formed as the racemate.
The added strain induced by the dibenzopyran ring system
presumably lowered the activation energy for racemization of
the atropic diastereomers. Fortunately, this side product can be
surpressed by protection of the tertiary alcohol as its THP ether
(5) Savard, J.; Brassard, P. Tetrahedron 1984, 40, 3455-64.
(6) Ireland, R. E.; Aristoff, P. A.; Hoyung, C. F. J. Org. Chem. 1979,
44, 4318-22.
(7) Freskos, J. N.; Morrow, G. W.; Swenton, J. S. J. Org. Chem. 1985,
50, 805-10.
(8) (a) Wallace, T. W. Org. Biomol. Chem. 2006, 4, 3197-210. (b)
Shimizu, H.; Nagasaki, I.; Saito, T. Tetrahedron 2005, 61, 5405-32. (c)
McCarthy, M.; Guiry, P. J. Tetrahedron 2001, 57, 3809-44.
J. Org. Chem, Vol. 72, No. 26, 2007 10221

SCHEME 2. Resolution of Atropic Isomers via Derivatization and Crystallizaton
SCHEME 3. Cleavage of the Menthyl Carbamate
1
1528, 1355 cm-1; H NMR (400 MHz, CDCl3) δ 7.90 (dd, J )
8.2, 1.2 Hz, 1H), 7.44 (dd, J ) 8.0, 1.2 Hz, 1H), 7.31-7.35 (m,
5H), 7.23-7.29 (m, 3H), 7.13-7.18 (m, 4H), 6.99 (d, J ) 7.9 Hz,
followed by saponification and acidic workup [56% yield from
14-(aS)]. Again, conversion back to its menthyl carbamate 14-
(aS) confirmed no racemization had occurred under the reaction
process (83%, >20:1 dr).
In summary, the efficient synthesis of tetra-ortho-substituted
biaryl compounds has been reported utilizing propargyl tertiary
alcohols as dienophiles. A range of substituents is tolerated for
the tertiary alcohols; however, cyclic dienes are required to
facilitate effective cycloaddition. Facile resolution of the Diels-
Alder adduct 12 provided a rapid synthesis of enantiomerically
enriched biaryls 14 and 15. Continued exploration into the scope
of the DAB strategy will be reported in due course.
1H), 6.63 (dd, J ) 8.0, 0.6 Hz, 1H), 3.74 (s, 3H), 2.65 (s, 1H); 13
C
NMR (100 MHz, CDCl3) δ 157.6, 150.6, 147.0, 144.4, 144.3, 136.9,
133.8, 133.0, 128.3, 128.1, 128.0, 127.8, 127.7, 127.6, 127.4, 127.0,
124.4, 123.4, 122.0, 109.9, 82.9, 56.3; HRMS (CI+) calcd for
C26H20NO4Cl (M + H) 445.1081, found 445.1078.
Anilino Alcohol 12. To a stirred solution of 4f (2.78 g, 6.23
mmol) and glacial acetic acid (62.4 mL) was added Zn dust (2.04
g, 31.2 mmol) at rt. After 2 h, the mixture was quenched with sat.
aq NaHCO3 (250 mL), diluted with EtOAc (200 mL), and washed
with NaHCO3 (200 mL), H2O (200 mL), and sat. aq NaCl (200
mL). The dried extract (MgSO4) was concentrated in vacuo and
purified by chromatography over silica gel, eluting with 50-80%
CH2Cl2/hexanes to give 12 (2.45 g, 5.86 mmol, 94%) as a white
crystalline solid. Mp 110-11 °C; IR (neat) 3528, 3333, 2825, 1623,
Experimental Section
Acetylene 2f. To a stirred solution of 1 (2.05 g, 11.3 mmol) and
THF (56.5 mL) was added LDA (11.3 mL, 11.3 mmol, 1.0 M in
THF/hexanes) at -78 °C. After 10 min, the solution was transferred
via cannulation into a stirred solution of benzophenone (3.09 g,
16.9 mmol) in THF (16.9 mL) at -78 °C. After 30 min, the dark
brown solution was allowed to warm to rt. After an additional 1 h,
the mixture was quenched with sat. aq NH4Cl (100 mL), diluted
with EtOAc (100 mL), and washed with H2O (100 mL) and sat. aq
NaCl (100 mL). The dried extract (MgSO4) was concentrated in
vacuo and purified by chromatography over silica gel, eluting with
25-75% CH2Cl2/hexanes to give 2f (3.16 g, 8.69 mmol, 77%) as
a white crystalline solid. Mp 134-35 °C; IR (neat) 3524, 3077,
1572 cm-1; H NMR (300 MHz, CDCl3) δ 7.16-7.31 (m, 11H),
1
6.99 (t, J ) 8.0 Hz, 1H), 6.98 (dd, J ) 8.3, 1.0 Hz, 1H), 6.73 (dd,
J ) 7.9, 1.0 Hz, 1H), 6.66 (dd, J ) 8.0, 1.0 Hz, 1H), 6.54 (dd, J
) 8.0, 1.1 Hz, 1H), 4.59 (br s, 1H), 3.73 (s, 3H), 3.17 (br s, 2H);
13C NMR (100 MHz, CDCl3) δ 158.3, 147.1, 146.9, 146.3, 145.1,
135.8, 129.2, 128.7, 127.83, 127.81, 127.6, 127.5, 126.9, 126.8,
124.1, 123.3, 123.1, 120.0, 114.2, 110.6, 82.9, 56.4; HRMS (CI+)
calcd for C26H22NO2Cl (M + H) 415.1339, found 415.1359.
Carbamates 14-(aR) and 14-(aS). To a stirred solution of 12
(1.54 g, 3.71 mmol), DMAP (45.3 mg, 0.371 mmol), and pyridine
(18.6 mL) was slowly added (-)-menthyl chloroformate (4.06 g,
3.94 mL, 18.5 mmol) at 0 °C. After 1 h, the mixture was quenched
with NH4Cl (60 mL), diluted with Et2O (80 mL), and washed with
NH4Cl (60 mL), H2O (2 × 60 mL), and sat. aq NaCl (60 mL). The
dried extract (MgSO4) was purified by chromatography over silica
gel, eluting with 50-75% CH2Cl2/hexanes. The mixture of dia-
stereomers was crystallized from hot hexanes to give 14-(aR) (996
mg, 1.67 mmol, 45%) as white crystals, and after recrystallization
of the mother liquor, 14-(aS) (975 mg, 1.63 mmol, 44%) was
obtained. 14-(aR) isomer: Mp 162-163 °C; [R]23D -77.6 (c 2.08,
1
2220, 1531 cm-1; H NMR (400 MHz, CDCl3) δ 7.97 (dd, J )
8.2, 1.4 Hz, 1H), 7.75-7.77 (m, 4H), 7.73 (dd, J ) 8.2, 1.0 Hz,
1H), 7.39-7.44 (m, 5H), 7.29-7.35 (m, 2H), 3.11 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 151.0, 144.1, 139.1, 133.8, 128.9, 128.5,
128.0, 126.2, 122.9, 117.8, 105.7, 79.3, 75.3; HRMS (CI+) calcd
for C21H15NO3Cl (M + H) 364.0740, found 364.0748.
Biaryl 4f. To a pressure vessel containing 2f (3.16 g, 8.69 mmol)
and xylenes (17.4 mL) was added diene 3 (2.87 g, 3.01 mL, 26.1
mmol) at rt. The mixture was heated at 145 °C for 36 h. The crude
material was purified by chromatography over silica gel, eluting
with 10-40% CH2Cl2/hexanes to give 4f (2.78 g, 6.23 mmol, 72%)
as a yellow crystalline solid. Mp 152-53 °C; IR (neat) 3552, 3053,
CHCl3); IR (neat) 3569, 3414, 2954, 1727, 1575 cm-1; H NMR
(400 MHz, CDCl3) δ 7.86 (d, J ) 7.7 Hz, 1H), 7.35 (t, J ) 8.1
Hz, 1H), 7.18-7.33 (m, 11H), 7.08 (d, J ) 7.9 Hz, 1H), 6.99 (d,
1
10222 J. Org. Chem., Vol. 72, No. 26, 2007

J ) 7.7 Hz, 1H), 6.66 (d, J ) 7.9 Hz, 1H), 5.79 (s, 1H), 4.54 (td,
J ) 10.9, 4.4 Hz, 1H), 3.67 (s, 3H), 2.70 (s, 1H), 2.03 (d, J ) 11.7
Hz, 1H), 1.65-1.72 (m, 3H), 1.27-1.33 (m, 1H), 0.93-1.13 (m,
3H), 0.97 (d, J ) 6.5 Hz, 3H), 0.85 (d, J ) 7.0 Hz, 3H), 0.74 (d,
J ) 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.0, 153.1,
146.8, 146.1, 145.9, 138.0, 134.8, 128.9, 128.1, 127.9, 127.8, 127.7,
127.6, 127.5, 127.4, 126.9, 123.9, 123.5, 122.6, 117.9, 110.4, 83.5,
74.8, 56.2, 47.3, 41.5, 34.3, 31.4, 26.7, 24.1, 22.1, 20.5, 17.40;
HRMS (EI+) calcd for C37H40NO4Cl (M + H) 597.2646, found
122.8, 117.7, 110.6, 83.5, 75.1, 56.3, 47.1, 41.1, 34.3, 31.4, 25.9,
23.2, 22.1, 21.1, 16.3; HRMS (EI+) calcd for C37H40NO4Cl (M +
H) 597.2646, found 597.2651.
Acknowledgment. Financial support was provided by the
National Science Foundation (CHE-0549884) and OSU (Pipe-
line Fellowship and Tartar Fellowships for B.O.A.). The authors
would also like to thank Professor Max Deinzer (OSU) and Dr.
Jeff Morre´ (OSU) for mass spectral data, Dr. Lev N. Zakharov
for X-ray crystallographic services, and Dr. Roger Hanselmann
(Rib-X Pharmaceuticals) for his helpful discussions.
597.2642. 14-(aS) isomer: Mp 88-90 °C; [R]23 +18.8 (c 2.14,
D
1
CHCl3); IR (neat) 3556, 3415, 2955, 1727, 1575 cm-1; H NMR
(400 MHz, CDCl3) δ 7.94 (br s, 1H), 7.36 (t, J ) 8.1 Hz, 1H),
7.19-7.34 (m, 11H), 7.05 (dd, J ) 7.9, 0.7 Hz, 1H), 7.01 (d, J )
8.1 Hz, 1H), 6.68 (d, J ) 8.0 Hz, 1H), 6.01 (s, 1H), 4.61 (td, J )
10.9, 4.3 Hz, 1H), 3.70 (s, 3H), 2.73 (s, 1H), 1.97-2.06 (m, 3H),
1.73 (d, J ) 11.7 Hz, 2H), 1.49-1.54 (m, 1H), 1.33-1.41 (m,
1H), 1.01 (d, J ) 7.0 Hz, 3H), 0.94 (d, J ) 6.4 Hz, 3H), 0.88-
1.16 (m, 2H), 0.85 (d, J ) 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 158.2, 153.2, 146.8, 146.4, 145.7, 138.3, 134.8, 128.9,
128.8, 128.1, 127.9, 127.8, 127.7, 127.4, 127.3, 126.8, 123.9, 123.4,
Supporting Information Available: All remaining experimental
1
procedures are provided, including H and 13C spectra, of all new
compounds, as well as crystallographic data with details of data
collections and refinements for crystal structures of the compounds
14-(aR) and 15-(aR) and the corresponding CIF files. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO070812E
J. Org. Chem, Vol. 72, No. 26, 2007 10223