Synthesis of tetra-ortho-substituted, phosphorus-containing and carbonyl-containing biaryls utilizing a Diels-Alder approach

Article abstract of DOI:10.1021/ja071163r

The application of the Diels-Alder approach to biaryls (DAB) is described for the synthesis of tetra-ortho-substituted biaryl compounds containing orthogonally functionalized substituents. The syntheses of phosphorus- containing, disubstituted alkynes and

Full text of DOI:10.1021/ja071163r

Published on Web 06/29/2007
Synthesis of Tetra-ortho-substituted, Phosphorus-Containing
and Carbonyl-Containing Biaryls Utilizing a Diels-Alder
Approach
Bradley O. Ashburn, Rich G. Carter,* and Lev N. Zakharov†
Contribution from the Department of Chemistry, 153 Gilbert Hall, Oregon State UniVersity,
CorVallis, Oregon 97331
Received March 8, 2007; E-mail: rich.carter@oregonstate.edu
Abstract: The application of the Diels-Alder approach to biaryls (DAB) is described for the synthesis of
tetra-ortho-substituted biaryl compounds containing orthogonally functionalized substituents. The syntheses
of phosphorus-containing, disubstituted alkynes and carbonyl-containing, disubstituted alkynes were
accomplished in two to three steps from commercially available reagents. Subsequent Diels-Alder
cycloadditions with a range of oxygenated dienes yielded the target biaryls. Further functionalization through
palladium-couplings is demonstrated on the phosphorus-containing biaryls. In addition, selective manipulation
of each of the remaining ortho substituents on the phosphorus-containing biaryls is demonstrated. One of
these phosphorus-containing derivatives is utilized as a highly active catalyst for Suzuki coupling. For the
carbonyl-containing series, a wide range of dienophile substituents were screened including esters, ketones,
and amides. The key Diels-Alder cycloadditions proceeded smoothly with the commercially available
1-methoxy-1,3-cyclohexadiene to yield the resultant tetra-ortho-substituted biaryls with excellent regiose-
lectivity. The scope of the cycloaddition process was also explored on the carbonyl-containing dienophiles
with a series of cyclic dienes. Acyclic dienes were also screened; however, they did not prove effective in
the Diels-Alder process with the carbonyl-containing acetylenes. The ability to isolate enantiomerically
pure biaryl atropisomers using a benzyl oxazolidinone is disclosed. Finally, the subsequent conversion to
an axially chiral anilino alcohol is also reported.
Introduction
of our work utilizing phosphorus-containing and carbonyl-
containing disubstituted aryl acetylenes.
The synthesis via the aryl-aryl σ linkage of highly substituted
biaryl compounds, particularly structures containing four ortho
substituents, has generated considerable synthetic attentions
primarily through the use of various transition metal-mediated
methods to form the linking σ bond.1-3 This task has long been
considered one of the premier challenges in the construction of
complex polyaromatic systems.4 An alternative approach to their
construction has been reported by our laboratory5 and others6
involving a Diels-Alder reaction of suitably functionalized,
disubstituted acetylenes. In this paper, we disclose a full account
Results and Discussion
Phosphorus-Containing Chloro Series. Our initial forays
into this field started from the alkyne,7 available in one step
from the commercially available 2-chloro-6-nitro-benzaldehyde
using the Ohira-Bestmann reagent8 (K2CO3, MeOH, 96%)
(Scheme 1). After some experimentation, we discovered that
use of lithium diispropylamide (LDA) followed by addition of
0.8 equiv of the requisite phosphorus electrophile [Ph2P(O)Cl
or (EtO)2P(O)Cl] gave excellent yields of the disubstituted
acetylenes 2a and 2b. Use of alternate bases (n-BuLi, NaH,
KHMDS, LiHMDS, TBAF, i-PrMgCl) led to only trace amounts
of the desired product. We are not certain at this time why LDA
is uniquely capable in the deprotontation of these terminal
alkynes. Next, we embarked on the crucial Diels-Alder process.
We hypothesized that that the Brassard diene 39 would be well-
† Director of X-ray Crystallographic Facility, Department of Chemistry,
Oregon State University, Corvallis, Oregon 97331 and Department of
Chemistry, University of Oregon, Eugene, Oregon 97403. E-mail: lev@
uoregon.edu.
(1) For a recent review of the area, see: Wallace, T. W. Org. Biomol. Chem.
2006, 4, 3197-210.
(2) Miyaura, N. Top. Curr. Chem. 2002, 219, 1-241.
(3) For alternative methods, See: Nishida, G.; Suzuki, N.; Noguchi, K.; Tanaka,
K. Org. Lett. 2006, 8, 3489-3492.
(4) (a) Montoya-Pelaez, P. J.; Uh, Y.-S.; Lata, C.; Thompson, M. P.; Lemieux,
R. P.; Crudden, C. M. J. Org. Chem. 2006, 71, 5921-5929. (b) Milne, J.
E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 13028-13032.
(5) Ashburn, B. O.; Carter, R. G. Angew. Chem., Int. Ed. 2006, 45, 6737-
6741.
(6) (a) Knolker, H.-J.; Baum, E.; Hopfmann, T. Tetrahedron Lett. 1995, 36,
5339-42. (b) Bateson, J. H.; Smith, C. F.; Wilkinson, J. B. J. Chem. Soc.
Perkin Trans. I 1991, 651-653. (c) Kanakam, C. C.; Mani, N. S.;
Ramanathan, H.; Subba Rao, G. S. R. J. Chem. Soc., Perkin Trans. I 1989,
1907-1913. (d) Liu, Y.; Lu, K.; Dai, M.; Wang, K.; Wu, W.; Chen, J.;
Quan, J.; Yang, Z. Org. Lett. 2007, 9, 805-808.
(7) (a) Naffziger, M. R.; Ashburn, B. O.; Perkins, J. R.; Carter, R. G. J. Org.
Chem., published online June 29, 2007 http://dx.doi.org/10.1021/jo070740r.
For additional use of the 2-chloro-6-nitro-phenylacetylene (1), see: (b)
Ashburn, B. O.; Carter, R. G. J. Org. Chem., published online June 29,
2007 http://dx.doi.org/10.1021/jo070812e.
(8) (a) Ohira, S. Synth. Commun. 1989, 19, 561-564. (b) S. Mu¨ller, S.; Liepold,
B.; Roth, G. J.; Bestmann, J. SYNLETT 1996, 521-522. For preparation
of 6, see also: (c) Goundry, W. R. F.; Baldwin, J. E.; Lee, V. Tetrehedron
2003, 59, 1719-1729. (d) Kitamura, M.; Tokynaga, M.; Noyori, R. J. Am.
Chem. Soc. 1995, 117, 2931-2932.
(9) Savard, J.; Brassard, P. Tetrahedron 1984, 40, 3455-3464.
9
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J. AM. CHEM. SOC. 2007, 129, 9109-9116
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A R T I C L E S
Ashburn et al.
Scheme 3. Synthesis of Brominated, Phosphorus-Containing
Scheme 1. Synthesis of First-Generation Phosphorus-Containing
Biaryls
Dienophiles
Phosphorus-Containing Bromo Series. On the basis of the
inability to couple the C-Cl bond, the logical solution that we
chose to employ was to substitute a more reactive halogen
substituent. Consequently, the bromo-acetylene 12 needed to
be synthesized (Scheme 3). While the 2-bromo-6-nitro-benzal-
dehyde 10 was known, its preparation required a tedious three-
step protocol.13 We instead chose to exploit chemistry first
reported by scientists at Pfizer involving the dimethyl acetal of
DMF followed by cleavage of the resultant enamine with
NaIO4.7,14 Unfortunately, use of the identical reaction conditions
on the 2-bromo-6-nitro-toluene (8) did not cleanly generate the
desired aldehyde 10. We did discover, however, that if the
conditions were modified by cooling of the intermediate enamine
9 solution to 0 °C and by rapidly adding it to a vigorously stirred
solution of NaIO4 at 0 °C, the undesired impurities were
completely suppressed.15 This one-pot protocol does not require
the isolation of the intermediate enamine 9 and has proven quite
effective in our hands. Subsequent alkyne formation with the
Ohira-Bestmann reagent 118 provided 12. Again, deprotonation
with LDA followed by addition of the phosphorus electrophile
[Ph2P(O)Cl, (c-C6H11)2P(O)Cl, or (EtO)2P(O)Cl] gave the
desired disubstituted alkynes 13a-c.
suited for this transformation. Gratifyingly, the Diels-Alder
process proceeded quite cleanly via the intermediate 4. This
intermediate was not isolated (as it proved quite unstable), and
in situ cleavage of the silyl ether 4 to induce aromatization was
accomplished with TBAF to yield the biaryls 5a and 5b in good
yield (60-84%). Conclusive structural assignment of biaryl 5b
was obtained via X-ray crystallographic analysis (Figure 1).
We were gratified to observe that the Diels-Alder reactions
again proceeded well (Scheme 4). We were able to employ a
range of dienes 15, 17, and 19 in addition to the Brassard diene
3. The generality of this approach clearly demonstrates the
unique power of the Diels-Alder reaction to construct even
the most congested of biaryl linkages. X-ray crystal structures
of biaryls 14a and 14c were determinedsfurther confirming
the regiochemical outcome of the Diels-Alder process. Interest-
Figure 1. ORTEP representation of the X-ray structure of biaryl 5b.
Next, we explored the potential palladium-coupling of the
aryl chloride (Scheme 2). Despite our considerable efforts with
a wide range of catalyst systems,10-12 we were unable to effect
C-Cl insertion on biaryl 6. Two possible explanations can be
offered for this lack of reactivity: the increased steric require-
ment of the four ortho substituent or the disruptive coordinating
ability of the phosphine-oxide.
(10) (a) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020-
4028. (b) Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc. 2002,
124, 6343-6348. (c) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123,
2719-2724.
(11) (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176-4211.
(b) Minutolo, F.; Antonello, M.; Bertini, S.; Rapposelli, S. Rossello, A.;
Sheng, S.; Carlson, K. E.; Katzenellenbogen, J. A.; Macchia, M. Bioorg.
Med. Chem. 2003, 11, 1247-1257.
Scheme 2. Attempted Palladium-Coupling of Chlorinated
Phosphorus-Containing Biaryls
(12) (a) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 4685-4696. (b) Walker, S. D.; Barder, T. E.;
Martinelli, J. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 43, 1871-
1876. (c) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126,
13028-13032.
(13) Li, J.-S.; Fan, Y.-H.; Zhang, Y.; Marky, L. A.; Gold, B. J. Am. Chem. Soc.
2003, 125, 2084-2093.
(14) (a) Vetlino, M. G.; Coe, J. W. Tetrahedron Lett. 1994, 35, 219-222. (b)
Caron, S.; Vazquez, E.; Stevens, R. W.; Nahao, K.; Koike, H.; Murata, Y.
J. Org. Chem. 2003, 68, 4104-4107.
(15) Primarily, we observed the homologated aldehyde resulting from the
hydrolysis of the enamine intermediate as the predominate impurity.
9
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Diels
−
Alder Approach to Synthesis of Biaryls
A R T I C L E S
Table 1. Suzuki, Stille, and Negishi Couplings of Biaryls 14
Scheme 4. Synthesis of Second-Generation
Phosphorus-Containing Biaryls
R
Suzukia yield (%)
Stilleb yield (%)
Negishic yield (%)
Ph
c-C6H11
EtO
61
72
63
60
66
60
59
62
57
a Catalyst (20 mol %), 23 (3 equiv), KF (9 equiv), NMP, 100 °C, 16 h.
b Catalyst (20 mol %), 24 (3 equiv), CsF (9 equiv), NMP, 60 °C, 16 h.
c Catalyst (10 mol %), 25 (1.5 equiv), NMP/THF, 80 °C, 16 h.
Table 2. Variation of Negishi Couplings on Biaryl 14c
entry
Ar
−
ZnCla
yield (%)
a
b
c
d
e
f
4-methoxyphenylzinc chloride
3-methoxyphenylzinc chloride
2-methoxyphenylzinc chloride
2-methylphenylzinc chloride
2,6-dimethylphenylzinc chlorideb
pentafluorophenylzinc chloride
59
58
0
61
66
57
a Organozinc species was formed by addition of the in situ generated
organomagnesium species to a 1 M THF solution of anhydrous zinc chloride.
b Extended reaction time (48 h) was employed for this coupling.
Pd° system developed by the Fu laboratory gave positive results
in the coupling processes.10 We found that efficient Suzuki and
Stille couplings could be accomplished with the corresponding
phenyl boronic acid (24) and the tributylphenyl stannane (25).
These couplings, however, required high catalyst loading (20
mol %) and excess aryl metallo species (3 equiv) to proceed to
completion. In addition, we found very poor functional group
tolerance with substituted aryl boronic acids or aryl stannanes
routinely resulting in incomplete reaction and low chemical
yields. In contrast, we found that the organozinc species coupled
quite efficiently with reduced catalyst loading (10 mol %) and
phenylzinc chloride (26, 1.5 equiv).
ingly, Diels-Alder reaction of the monosubstituted alkyne 12
with Brassard diene 3 generates none of the expected biaryl
adduct 22; instead the enol ether 21 is formed in reasonable
yield (41%). This product was not observed with the 2-chloro
version but with the 3-chloro variant,7 thus demonstrating the
unique role that the halogen plays in the Diels-Alder process.
We next sought to demonstrate the feasibility of accomplish-
ing metal-mediated coupling on the resultant biaryls. The
pentasubstituted biaryls 14a-c were chosen for initial screening
(Table 1). We explored a range of Suzuki, Stille, and Negishi
conditions for accomplishing this transformationsincluding
Buchwald’s ligands,12 P(c-C6H11)3/Pd2(dba)3,11 Pd(dppf)Cl2, and
Pd(OAc)2/dppp.16 We were pleased to find that the (t-Bu3P)2-
It became clear that the Negishi conditions provided the
largest opportunity of substrate scope (Table 2). The dicyclo-
hexylphosphine oxide biaryl was selected for further exploration.
Good tolerance for substitution on the aryl ring was observed
with substitution in the ortho, meta, or para positions. One
exception to this observation is the failure of 2-methoxyphenyl
zinc chloride to undergo successful coupling. The problem
appears to be electronic in nature as additional steric substitution
(16) Shen, W. Tetrahedron Lett. 1997, 38, 5575-5578.
9
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A R T I C L E S
Ashburn et al.
Scheme 5. Further Functional Modification of Biaryls
Figure 2. ORTEP representation of the X-ray structure for biaryl 34‚HCl.
ortho to the organozinc species does not disrupt the palladium
coupling (entries d and e). In fact, the 2,6-dimethylphenyl zinc
chloride proved the most efficient substrate for this coupling
process. It should also be noted that electron-withdrawing
substituents are tolerated (entry f). The structures of compounds
28a, 28e, and 28f were confirmed by single-crystal X-ray
diffraction methods.
Further functionalization of the biaryl moiety was also
possible (Scheme 5). The nitro group can be easily reduced using
zinc in acetic acid (85%). Attempted hydrogenation of the nitro
compound 28e to the amino compound 29 gave complex
mixtures and low mass recovery [presumably due to irreversible
binding of the resultant phosphine-oxide amino alcohol (e.g.,
32) to the metal surface]. A wide range of conditions were
screened for the reduction of the phosphine oxide moiety. The
most common set of conditions typically used for this trans-
formation employs HSiCl3 and Et3N;17 however, these condi-
tions provided none of the desired phosphine; only extensive
decomposition was observed. We also screened several aluminum-
based reagents (e.g., LAH, AlH3) which again provided none
of the desired product. Instead, a small amount of the tri-ortho-
substituted biaryl 31 was isolated with selective C-P bond
cleavage. Fortunately, the desired reduction of the P-O bond
could be accomplished using conditions developed by Lawrence
and co-workers.18 Further manipulation of the functional groups
on the biaryls was possible. The benzyl ether could be readily
cleaved with BCl3 to provide the phenol 32 in good yield. Also,
the anilino group present in compounds 29 and 30 could be
reductively aminated using NaBH3CN and paraformaldehyde
to give the dimethylamino compounds 33 and 34. X-ray
crystallographic analysis of the hydrochloride salt of the
dimethylamino phosphine 34 is shown in Figure 2. Also,
attempted reduction of the phosphine oxide moiety in biaryl 33
(using the Lawrence conditions) gave low yield of the product
34 (38%) with a significant amount of recovered starting
material.
The dimethylamino phosphine 34 was screened for its
potential utility as a ligand in palladium-mediated processes
(Scheme 6). We were pleased to observe that it serves as a
highly active ligand for cross-coupling reactions. The synthe-
sized ligand 34 appears to be critical to the success for these
transformations as the experiment in the absence of phosphine
with boronic acid 35 and bromide 36 [5 mol % Pd(OAc)2, K3-
PO4, PhMe, 100 °C, 20 h] gave only a small amount (18%) of
the desired coupled material 37. The use of alternate phosphines
(e.g., PPh3) as a substitute ligand also gave inferior results. It
is significant to note that phosphine 34 is the sole compound
we have screened to date in this process, and yet it is already
(17) (a) Sie, X.; Zhang, T. Y.; Zhang, Z. J. Org. Chem. 2006, 71, 6522-6529.
(b) Sannicolo, F.; Benincori, T.; Rizzo, S.; Gladiali, S.; Pulacchini, S.; Zotti,
G. Synthesis 2001, 15, 2327-2336. (c) Miyashita, A.; Karino, H.;
Shimamura, J; Chiba, T.; Nagano, K.; Nohira, H.; Takaya, H. Chem. Lett.
1989, 10, 1849-1852.
(18) Coumbe, T.; Lawrence, N. J.; Muhammad, F. Tetrahedron Lett. 1994, 35,
625-628.
9
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Diels
−
Alder Approach to Synthesis of Biaryls
A R T I C L E S
Table 3. Synthesis of the Disubstituted, Carbonyl-Containing
Scheme 6. Utility of Ligand 34 in Cross-Coupling Reactions
Alkynes
entry
electrophile (Cl-E)
yield (%)
a
b
c
d
e
f
g
h
i
ClCO2Me
ClCO2Et
ClCO2CH2CCl3
ClC(O)-t-Bu
ClC(O)Ph
ClC(O)-p-Cl-C6H4
ClC(O)-p-NO2-C6H4
ClC(O)NMe2
ClC(O)NPh2
ClC(O)-N-morpholinyl
(-)-ClCO2-menthyl
92
91
68
74
67
59 (borsm)
35
65
56
89
63
61
j
k
l
able to perform comparably with the Buchwald’s N,N-dimethyl-
amino biaryl system19 in side-by-side experiments. We have
also demonstrated that ligand 34 can be utilized for carbon-
nitrogen bond formation. p-Anisidine (40) was cleanly coupled
with aryl iodides 41 and 43 to generate the disubstituted anilines
42 and 44 in excellent yields.20 Of note is the low ligand loading
(2 mol %) required to facilitate this transformation.
Table 4. Diels-Alder Reactions of Carbonyl-Containing
Acetylenes with 1-Methoxy-1,3-cyclohexadiene
Carbonyl-Containing Series. Given the success of the
phosphorus-containing series to generate sterically congested
biaryls, we sought to explore in more detail the scope of
electron-withdrawing groups tolerated on the acetylenes
including the possibility that the regiochemistry could be altered
by the selection of alternate groups on the alkyne. In particular,
we were interested in studying the effects of carbonyl moieties
as their added electron-withdrawing ability might perturb the
regiochemical outcome of the cycloaddition. The synthesis of
these compounds could be readily accomplished from the
previously mentioned alkyne 12. Treatment of the acetylene 12
with LDA followed by the addition of the various chlorofor-
mates, carbamyl chlorides, and acid chlorides yielded the
acetylenic carbonyl adducts 45a-l. We are able to construct
esters (entries a-c), ketones (entries d-g), and amides (entries
h-i) via this approach. In addition, we prepared the menthol
ester 45k and the benzyl oxazolidinone 45l via analogous
methods. The yields were generally good to excellent. One
limitation appears to be that strongly electron-withdrawing acyl
chlorides give low yields due to overaddition and other
uncharacterized impurities (entries f and g).
entry
R
yield (%)
a
b
c
d
e
f
g
h
i
OMe
OEt
82
85
64
81
71
64
OCH2CCl3
t-Bu
Ph
p-Cl-C6H4
p-NO2-C6H4
NMe2
complex mixture
75
72
83
NPh2
j
N-morpholinyl
biaryls 47 in good to excellent yield (64-85%). In the vast
majority of cases, a single regioisomer 47 was observed. We
attribute this fact to the directing ability the ortho-nitrophenyl
substitutionseven in the presence of additional strongly electron-
withdrawing groups. The regiochemistry of each biaryl product
47 was confirmed via HMBC analysis. Further confirmation
was obtained via X-ray crystallographic analysis of compound
47b. On certain aromatic ketone systems (entry f), a minor
amount (<10%) of the alternate regioisomer was observed. We
attempted to push the trend further with the more electron-
deficient alkyne 45g; however, a complex mixture of products
was observed in its cycloaddition (entry g). This Diels-Alder
process is believed to work via initial cycloaddition to the [2.2.2]
bicyclic adduct 46 followed by extrusion of ethylene to provide
aromatized biaryl 47. It should also be noted that we could
observe the bicyclic intermediate 46 if the reaction is conducted
at lower temperatures (50 °C, 16 h). In the case of the ethyl
ester 45b, the ratio between the two diastereomers is 1.5:1 as
With the dienophiles 45a-l in hand, we shifted our focus to
the exploration of the Diels-Alder cycloadditions (Table 4).
As we wanted to exploit a diene that is readily available, we
utilized the commercially available 1-methoxy-1,3-cyclohexa-
diene (17) for the cycloaddition process. We were pleased to
find that this approach for biaryl synthesis proved highly
effective. We observed formation of the tetra-ortho-substituted
(19) (a) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38, 2413-
2416. (b) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 9550-9561.
(20) Buchwald, S. L.; Ali, M. H. J. Org. Chem. 2001, 66, 2560-2565.
9
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A R T I C L E S
Ashburn et al.
Scheme 7. Diene Scope in the Carbonyl-Containing Diels-Alder
Reactions
Scheme 8. Use of Chiral Dienophiles in the Carbonyl-Containing
Diels-Alder Reactions
matographically separable atropic diastereomers 54-(aS) and 54-
(aR) (1:1). The absolute configuration of the atropic center of
chirality was assigned via the found X-ray crystal structure of
54-(aS) (Figure 3). The atropic integrity is maintained even with
prolonged heating at 130 °C (24 h, no change). Other oxazo-
lidinones were screened including the tert-butyl-derived oxazo-
lidinone and SuperQuat22 but led to similar results (1:1 ratio of
diastereomers).
judged by 1H NMR. These diastereomers are the result of diene
approach of the acetylene from the same side as the NO2 group
(endo approach) or the opposite side from the NO2 group (exo
approach). Subsequent heating at higher temperatures (130 °C,
16 h) did induce ethylene extrusion to produce the desired biaryl
47 as a single regioisomer.
Synthesis of Biaryl-Derived, Enantioenriched Amino
Alcohol and Lactam. With rapid entry into the axially chiral
biaryl compounds via the Diels-Alder approach, we wanted
to explore the ability to additionally functionalize the scaffold.
We were pleased to find that reduction of the oxazolidinone
54-(aS) with LiBH4, MeOH at 0 °C generated the alcohol 55 in
good yield (Scheme 9). Use of alternate reduction systems (e.g.,
LiAlH4) led to complex mixtures. Reduction of both the nitro
and the carbonyl moieties may be accomplished in a single step
by simply conducting the same reduction at reflux to yield the
anilino alcohol 56 in reasonable yield (64%). Amino alcohol
56 represents one of the first reported examples of a potential
organocatalyst possessing solely axial chiralitysparticularly with
anilino-derived structures.23 Recent reports on the organocata-
lytic ability of anilines have been disclosed.24 Alternatively, we
found that reduction of the nitro moiety 54 with Zn/AcOH
induced formation of the highly strained lactam 57 in modest
yield. The structure of ent-57 (Figure 4) was determined by
single-crystal X-ray diffraction methods. It should be noted
from the X-ray structure that the bromide and methoxy moieties
are oriented significantly out of the planeswith a dihedral angle
between the bromide and the methoxy group of 35.3° (with
respect to the plane created by the neighboring atoms,
Figure 4). Interestingly, reduction of the nitro moiety with
We also explored the diene scope of this protocol using the
dienophile 45b (Scheme 7). In addition to the mono-oxygenated
cyclic diene 48, we found that 1,3-bis-oxygenation is tolerated
in the cycloaddition process (dienes 19 and 51). The diene 5121
was employed to provide benzyloxy substitution at the ortho
phenolic position. We initially screened acyclic dienes such as
Brassard’s diene, but no cycloadduct was observed. It is apparent
from our efforts that a cyclic diene moiety is required to achieve
effective cycloaddition with these carbonyl-containing dieno-
philes 45. We are unsure of an exact rationale for this result;
however, one possible explanation is that the acyclic dienes (e.g.,
Brassard’s diene 3) may undergo a stepwise or [2+2] addition
to the acetylene followed by decomposition of the resultant
intermediate. Support for this possibility can be seen in the fact
that consumption of the dienophile is observed with diene 3.
Additionally, some of the carbonyl-containing dienophiles 45
have proven significantly more sensitive than the phosphorus-
containing series; the esters 45a-c require purification on
Florisil and the oxazolidinone 45l is purified on SiO2 in the
presence of 1% Et3N in order to avoid decomposition.
Synthesis of Atropisomers. We are beginning to expand the
scope of this Diels-Alder process to include the rapid synthesis
of enantiomerically pure atropic isomers (Scheme 8). Use of
the menthol ester 45k did generate a 1:1 mixture of diastere-
omeric atropisomers (78%); however, we were unable to
separate the two compounds. Fortunately, when the benzyl
oxazolidinone-containing dienophile 45l was allowed to react
with the commercially available diene 17, we observed chro-
(22) Bull, S. D.; Davies, S. G.; Jones, S.; Sanganee, H. J. J. Chem. Soc., Perkin
Trans. 1999, 1, 387-398.
(23) Despite the wealth of research that has been directed toward organocatalysis,
relatively little attention has been focused on the use of axial chirality for
asymmetric organocatalytic induction. (a) For a recent series of reviews in
the area, see: Acc. Chem. Res. 2004, 37(8), 487-631. (b) It is important
to acknowledge the pioneering work by Maruoka in the area of axial chiral
organocatalysts. Kano, T.; Tokuda, O.; Takai, J.; Maruoka, K. Chem. Asian
J. 2006, 1, 210-215.
(24) (a) Dirksen, A.; Hackeng, T. M.; Dawson, P. E. Angew. Chem., Int. Ed.
2006, 45, 7581-7584. (b) Dirksen, A.; Dirksen, S.; Hackeng, T. M.;
Dawson J., P. E. J. Am. Chem. Soc. 2006, 128, 15602-15603. (c) See
also: Borman, S. Chem. Eng. News 2006, 84 (49), 11.
(21) Diene 46 could be readily prepared from 1,3-cyclohexanedione in two steps
[BnOH, PTSA (2.5 mol %), PhMe, Dean-Stark trap, reflux, 20 h, 86%;
LDA, THF, -78 °C, then TMSCl, 99%]. See ref 7.
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9114 J. AM. CHEM. SOC. VOL. 129, NO. 29, 2007

Diels−Alder Approach to Synthesis of Biaryls
A R T I C L E S
Figure 3. ORTEP representation of the X-ray structure of biaryl 54-(aS).
Figure 4. ORTEP representation of the X-ray structure of lactam ent-57.
Scheme 9. Synthesis of Potential Organocatalysts
to work better on the more substituted systems. Additionally,
the strong directing ability of the ortho nitro moiety, even in
the presence of ketones, esters, and amides is noteworthy.
We have demonstrated the utility of this methodology for
the synthesis of a novel ligand system for C-C and C-N
couplings. The first-generation ligand 34 has demonstrated early
potential for facilitating challenging cross-couplings. This
example embodies the power of the DAB methodologysthe
ability to construct sterically demanding biaryl structures not
accessible from traditional metal-mediated methods. This meth-
odology provides an ideal complement to the powerful coupling
technologies developed by Fu, Buchwald, Hartwig, and others1,2
for the synthesis of complex biaryl structures. The combination
of these two technologies has the potential to lead to the
development of new ligand systems that may facilitate cross-
coupling processes not currently accessible from the existing
ligand systems.
The carbonyl-containing biaryl series has been exploited for
the synthesis of a series of ester-, ketone-, and amide-containing,
tetra-ortho-substituted biaryls. The strong directing ability of
the ortho nitro moiety is able to guide the cycloaddition in the
presence of an array of carbonyl derivatives. The first reported
case of enantioenriched biaryls from our DAB protocol is
demonstrated using a benzyl oxazolidinone. Subsequent conver-
sion to a series of derivatives, including the axially chiral, biaryl
anilino alcohol 56, showcases the flexibility of this methodology.
Future applications of this technology will be reported in due
course.
Zn in aqueous HOAc produced the dehalogenated lactam
derivative 58.
Conclusion
This article demonstrates the utility of the DAB methodology
to provide highly functionalized, useful biaryls in an expedient
fashion (typically three to four steps). We have successfully
synthesized entire classes of biaryl compounds that would not
be readily accessible from alternative methods. In fact, the
successful construction of biaryl compounds possessing four
different atoms (N, Cl/Br, O, and P for the phosphorus series
and N, Br, O, and C for the carbonyl series) at the four ortho
positions has not been accomplished by any other method. One
intriguing feature of these Diels-Alder processes is their ability
to construct sterically challenging functionality under quite mild
conditions. In many cases, the cycloaddition sequence appears
Acknowledgment. Financial support was provided by the
National Science Foundation (CHE-0549884) and Oregon State
University (OSU) (Pipeline Fellowship and Tartar Fellowship
for B.O.A.). We also thank Professor Max Deinzer (OSU) and
9
J. AM. CHEM. SOC. VOL. 129, NO. 29, 2007 9115

A R T I C L E S
Ashburn et al.
Dr. Jeff Morre´ (OSU) for mass spectral data, and Dr. Roger
Hanselmann (Rib-X Pharmaceuticals) for his helpful discussions.
for crystal structures of the compounds 5b, 14a, 14c, 28a, 28e,
28f, 34‚HCl, 47b, 54-(aS), ent-57 and the corresponding CIF
files. This material is available free of charge via the Internet
at http://pubs.acs.org.
Supporting Information Available: All experimental proce-
dures; 1H and 13C spectra of all new compounds; crystal-
lographic data with details of data collections and refinements
JA071163R
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9116 J. AM. CHEM. SOC. VOL. 129, NO. 29, 2007