Diels-alder approach to biaryls: Elucidation of competing tandem [2+2] cycloaddition/[1,3] sigmatropic shift pathway

Article abstract of DOI:10.1021/jo801245a

(Chemical Equation Presented) Reaction of 2-halo-6-nitrophenylacetylene with an electron deficient diene gives rise to a [4+2] cycloaddition/ cycloreversion biaryl product and a bicyclo[4.2.0]octadiene resulting from a competing [2+2] cycloaddition pathway. The cyclobutene can be opened to give a mixture of cyclooctatriene and biaryl in varying amounts depending on heat and light exposure. The conversion of the cyclobutene into biaryl occurs through a [1,3] sigmatropic carbon shift followed by [4+2] cycloextrusion of ethylene gas.

Full text of DOI:10.1021/jo801245a

Diels-Alder Approach to Biaryls: Elucidation of Competing
Tandem [2+2] Cycloaddition/[1,3] Sigmatropic Shift Pathway
Bradley O. Ashburn, Rich G. Carter,* and Lev N. Zakharov†
Department of Chemistry, 153 Gilbert Hall, Oregon State UniVersity, CorVallis, Oregon 97331
rich.carter@oregonstate.edu
ReceiVed June 12, 2008
Reaction of 2-halo-6-nitrophenylacetylene with an electron deficient diene gives rise to a [4+2]
cycloaddition/cycloreversion biaryl product and a bicyclo[4.2.0]octadiene resulting from a competing
[2+2] cycloaddition pathway. The cyclobutene can be opened to give a mixture of cyclooctatriene and
biaryl in varying amounts depending on heat and light exposure. The conversion of the cyclobutene into
biaryl occurs through a [1,3] sigmatropic carbon shift followed by [4+2] cycloextrusion of ethylene gas.
Introduction
electron donating group(s) and/or the dienophile contains an
electron withdrawing group(s) have been shown to progress
under much more reasonable conditions. Additionally, rigidify-
ing the conformation of the diene has also been shown to have
a dramatic effect on the rate of the reaction by keeping the diene
in the reactive s-cis conformation.6 A classical example
employed in undergraduate organic laboratories is the reaction
of maleic anhydride (2) with cyclopentadiene (1) (eq 2).7
Cyclopentadiene (1) is commonly prepared via retro-Diels-Alder
cycloaddition (often called a cycloreversion) of dicyclopenta-
diene (4) (eq 3).8 Both forward and reverse cycloadditions have
found considerable use in organic synthesis.9
Since its discovery 80 years ago by Diels and Alder,1 the
[4+2] cycloaddition has proven to be a powerful tool for the
construction of complex molecular architectures. The widely
accepted mechanism for this transformation involves a cyclic
concerted reorganization of the electrons between a diene (4π
electrons) and a dienophile (2π electrons).2 Analysis of the
molecular orbitals for this transformation has shown that the
highest occupied molecular orbital (HOMO) from the diene
typically interacts with the lowest unoccupied molecular orbital
(LUMO) of the diene.3 Inverse demand Diels-Alder processes
have also been utilized in which an electron-rich dienophile and
an electron-poor diene are employed.4 While the parent reaction
between 1,3-butadiene and ethylene requires forcing conditions
to proceed (eq 1),2,5 systems in which the diene contains an
† 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) Diels, O.; Alder, K. Liebigs Ann. Chem. 1928, 460, 98–122.
(2) (a) Houk, K. N.; Lin, Y. T.; Brown, F. K. J. Am. Chem. Soc. 1986, 108,
554–556. (b) Houk, K. N.; Li, Y.; Evanseck, J. D. Angew. Chem., Int. Ed. Engl.
1992, 31, 682–708. (c) Li, Y.; Houk, K. N. J. Am. Chem. Soc. 1993, 115, 7478–
7485. (d) Houk, K. N.; Gonzalez, J.; Li, Y. Acc. Chem. Res. 1995, 28, 81–90.
(e) Goldstein, E.; Beno, B.; Houk, K. N. J. Am. Chem. Soc. 1996, 118, 6036–
6043. (f) Karadakov, P. B.; Cooper, D. L.; Gerratt, J. J. Am. Chem. Soc. 1998,
120, 3975–3981. (g) Sakai, S. J. Phys. Chem. A 2000, 104, 922–927.
(3) (a) Daniel, H.; Jones, G. O.; Houk, K. N. AdV. Synth. Cat. 2006, 348,
2337–2361. (b) Sauer, J. Angew. Chem., Int. Ed. 1967, 6, 16–33. (c) Holmes,
H. L. Org. React. 1958, 4, 60–173.
Our laboratory has utilized the combination of a Diels-Alder
cycloaddition and a cycloreversion to provide access to a wide
(4) Boger, D. L.; Patel, M. Prog. Heterocycl. Chem. 1989, 1, 30–64.
10.1021/jo801245a CCC: $40.75
Published on Web 08/22/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7305–7309 7305

Ashburn et al.
range of highly substituted biaryl compounds.10,11 We have
primarily exploited the use of o-nitrophenyl-substituted alkynes
6 as our dienophile component and oxygenated dienes (e.g., 5)
for the 4π component in this Diels-Alder approach to biaryls
(DAB) (eq 1).10 These substrates have shown a remarkable
ability to construct highly congested biaryl linkages 8smany
of which possess four ortho substitutents with respect to the
central biaryl bond. We have presumed that this transformation
proceeded through an initial [4+2] cycloaddition to generate
the [2.2.2] bicycle 7 followed by [4+2] cycloreversion to
provide the biaryl 8. We have isolated what we believe to be
the [2.2.2] bicyclic intermediate 7 and shown that heating of
this intermediate does cleanly generate the biaryl 8. Interestingly,
our attempts to induce cycloaddition reactions with the parent
1,3-cyclohexadiene (9) have not met with success to date (eq
5). We are unsure at this juncture as to the exact rationale for
lack of clean cycloaddition using diene 9. In an effort to explore
the scope of our DAB strategy, the extension of our DAB
strategy to electron-deficient dienes such as 1-carbomethoxy-
cyclohexadiene (11)12 seemed like a logical step (eq 6). This
diene has been shown to undergo [4+2] cycloadditions with
electron rich dienophiles such as ynamine13a,b in an inverse
electron demand Diels-Alder process. Herein, we disclose an
account of the reactivity and mechanistic underpinings of diene
11 with our o-nitrophenyl alkynes 6.
SCHEME 1. Cycloaddition Reactions of Acetylenes 13, 18,
and 21 with Dienes 11 and 5
prepared in two steps from methyl 4-bromocrotonate.12 Our
group has previously reported the one-step synthesis of alkyne
13 from the commercially available 2-chloro-6-nitrobenz-
aldehyde.10c Heating a mixture of the two reagents 11 and 13
at 140 °C in xylenes for 6 h resulted in the consumption of
starting materials and the formation of two products as a 1.3:1
mixture (14:15) based on crude 1H NMR analysis. The
compounds proved quite challenging to separate by standard
chromatographic techniques on a small scale; however, this
mixture could be purified via recrystallization from diethyl ether/
petroleum ether. On a large scale (>2 g), reasonable separation
Results and Discussion
(9) (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37,
388–401. (b) Trost, B. M.; Jiang, C. Synthesis 2006, 369–396.
We first elected to explore the initial reactivity of diene 11
with our chloro alkyne 13 (Scheme 1). The diene 11 can be
(10) (a) Ashburn, B. O.; Carter, R. G. Angew. Chem., Int. Ed. 2006, 45,
6737–6741. (b) Ashburn, B. O.; Carter, R. G.; Zakharov, L. N. J. Am. Chem.
Soc. 2007, 129, 9109–9116. (c) Naffziger, M. R.; Ashburn, B. O.; Perkins, J. R.;
Carter, R. G. J. Org. Chem. 2007, 72, 9857–9865. (d) Ashburn, B. O.; Carter,
R. G. J. Org. Chem. 2007, 72, 10220–10223. (e) Perkins, J. R.; Carter, R. G.
J. Am. Chem. Soc. 2008, 130, 3290–3291. (f) For a detailed discussion of the
importance of the o-nitro moiety, see: Ashburn, B. O.; Carter, R. G. Org. Biomol.
Chem. 2008, 6, 255–257. (g) Ashburn, B. O.; Rathbone, L. K.; Camp, E. H.;
Carter, R. G. Tetrahedron 2008, 64, 856–865.
(5) Nicholas, P. P.; Carroll, R. T. J. Org. Chem. 1968, 33, 2345–2349.
(6) For a recent study into the conformational selectivity in Diels-Alder
reactions, see: Bradley, A. Z.; Kociolek, M. G.; Johnson, R. P. J. Org. Chem.
2000, 65, 7134–7138.
(7) Allen, C. F. J. Chem. Educ. 1933, 10, 494–497.
(8) Moffett, R. B. Org. Synth. 1963, Coll. Vol. IV, 238–241.
7306 J. Org. Chem. Vol. 73, No. 18, 2008

Diels-Alder Approach to Biaryls
TABLE 1. Thermolysis and/or Photolysis of Cyclobutene 15
could be achieved via careful silica gel chromatography with
use of a CH2Cl2/hexanes gradient. We initially hypothesized
that compound 15 might be the [2.2.2] bicyclic adduct as shown
1
in eq 1; however, the H and 13C NMR did not support that
assignment. Fortunately, we were able to unambiguously
establish the structure of compound 15 by X-ray crystallographic
analysis.14 While this example represents the first reported case
from our laboratory of isolating a cyclobutene from our DAB
protocols, we have previously observed products that would
appear to have been constructed from a [2+2] cycloaddition
followed by electrocyclic ring opening.10b,c To the best of our
knowledge, there is only one previous report of a formal [2+2]
byproduct being formed with the diene 11.13a It should be noted
that no other regioisomers of either biaryl 14 or bicycle 15 were
isolated from the reaction. This selectivity speaks once again
to the powerful directing ability of the o-nitrophenyl moiety.10f
Our traditional DAB strategy has employed electron rich dienes
such as 1-methoxy-1,3-cyclohexadiene (5). This diene reacts
cleanly with alkyne 13 to provide solely biaryl 16 in excellent
yield (82%). None of the cyclobutene product 17 was observed
under these conditions. We have also explored the reactivity of
other alkynes with the diene 11. In the case of the analogous
2-bromo series (compound 18), we found a similar reactivity
pattern to the chloro alkyne 13. This result was somewhat
surprising, as we have previously observed divergent reactivity
between these two alkynes 13 and 18 with Brassard’s diene.10c
We also screened the non-halogenated alkene 21. Unfortunately,
purification of the products 22 and 23 from this reaction has
proven quite challenging. We can confirm the presence of the
key signals in the crude 1H NMR spectrum from this transfor-
mation for both the biaryl 2215 and the cyclobutene 23; however,
we have been unable to effectively purify these two compounds.
Fortunately, treatment of the mixture with Zn/AcOH affected
reduction of the nitro moiety with in situ cyclization to form
the known lactam 24.16 Finally, we investigated the performance
of the acetylenic ester 2510b in the cycloaddition process with
diene 11; however, a complex mixture of products was observed.
entry
a
conditions
ratio of biaryl 14:cyclooctatriene 25
1.1:1 (42% 14, 37% 25)
xylenes (0.5 M), xylenes,
160 °C, 6 h
26 (3 equiv), xylenes (0.5 M), 1.1:1 (no other products formed)
160 °C, 6 h
xylenes (0.5 M), 160 °C,
6 h (no light)
xylenes (0.5 M), 140 °C,
b
c
d
e
1.8:1 (47% 14, 26% 25)
no reaction
40 h
xylenes (0.5 M), 140 °C,
6 h (120W light bulb)
0:1 (83% 25)
To further probe this reaction pathway, we studied the
thermolysis and photolysis of cyclobutene 15 (Table 1). Interest-
ingly, treatment of cyclobutene 15 at more elevated temperatures
(160 °C, 6 h) resulted in the formation of two products: the
biaryl 14 and the 8-membered cyclooctatriene 25 (entry a). The
structure of cyclooctatriene 25 was conclusively established via
X-ray crystallographic analysis.17 It is important to note that
all of the cyclobutene 15 is consumed under these conditions.
One explanation for the formation of biaryl 14 could be a retro
[2+2] cycloaddition, which produces the initial starting materials
11 and 13 that could then recombine to form the [2.2.2] bicycle
27 (as well as the cyclobutene 15) followed by [4+2] cyclor-
eversion to yield the biaryl 14. To probe the validity of this
mechanism, the cyclobutene 15 was heated under identical
conditions except for the presence of the 1,3-bisoxygenated
diene 26 (entry b). Interestingly, these conditions produced biaryl
14 and cyclooctatriene 25 as the only observable products after
6 h at 160 °C. Diene 26 has been shown to react readily with
the alkyne 1310c and formation of the alternate biaryl 28 should
be observed if a cycloreversion of cyclobutene 15 to alkyne 13
is an active reaction pathway. This result would appear to rule
out the [2+2] cycloreversion of 15 under the reaction conditions.
Alternatively, a recent report of thermal [1,3] carbon shifts by
Baldwin18 led us to suspect that a [1,3] sigmatropic carbon shift
could also be an active pathway that would lead to biaryl 14.
These types of [1,3] shifts are common in rigid systems and
proceed via symmetry allowed suprafacial inversion of config-
uration.16 The inversion of configuration would not be noticed
in our case as the product is biaryl 14, which has all sp2
hybridized carbons. Inspection of the X-ray and DFT-level
geometry optimized19 structures shows that the orbitals in 15
are well-aligned to undergo a [1,3] carbon shift. We were also
intrigued to explore if the divergent pathways that were being
observed (biaryl formation and cyclooctatriene formation) could
be related to a photochemical process. Repeating the same initial
experiment (entry a) in the absence of light did improve the
(11) 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, 2188–2192. (b) McDonald, E.; Suksamrarn, A.; Wylie, R. D.
J. Chem. Soc., Perkin Trans. 1 1979, 1893–1900. (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, 536–544. (d) Boger, D. L.; Panek, J. S.; Duff, S. R. J. Am.
Chem. Soc. 1985, 107, 5745–5754. (e) Effenberger, F.; Ziegler, T. Chem. Ber.
1987, 120, 1339–1346. (f) Kanakam, C. C.; Mani, N. S.; Ramanathan, H.; Subba
Rao, G. S. R. J. Chem. Soc., Perkin Trans. 1 1989, 1907–1913. (g) Sain, B.;
Sandhu, J. S. J. Org. Chem. 1990, 55, 2545–2546. (h) Bateson, J. H.; Smith,
C. F.; Wilkinson, J. B. J. Chem. Soc., Perkin Trans 1 1991, 651–653. (i) Smith,
D. M.; Royles, B. J. L. J. Chem. Soc., Perkin Trans. 1 1994, 355–358. (j) D’Auria,
M. Tetrahedron Lett. 1995, 36, 6567–6570. (k) Knolker, H.-J.; Baum, E.;
Hopfmann, T. Tetrahedron Lett. 1995, 36, 5339–5342. (l) Avenoza, A.; Busto,
J. H.; Cativiela, C.; Peregrina, J. M. Synthesis 1995, 671–674. (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, 1267–1300. (o) Min, S.-
H.; Kim, Y.-W.; Choi, S.; Park, K. B.; Cho, C.-G. Bull. Korean Chem. Soc.
2002, 23, 1021–1022. (p) Hilt, G.; Smolko, K. I. Synthesis 2002, 686–92. (q)
Hilt, G.; Smolko, K. I.; Lotsch, B. V. Synlett 2002, 1081–1084. (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, 3575–3584. (u) Liu, Y.; Lu, K.; Dai, M.; Wang, K.;
Wu, W.; Chen, J.; Quan, J.; Yang, Z. Org. Lett. 2007, 9, 805–808.
(12) Pearson, A. J.; Sun, H. J. Org. Chem. 2007, 72, 7693–7700.
(13) (a) Ficini, J.; Dureault, A.; Revial, G.; Touzin, A. M. Tetrahedron Lett.
1974, 1025–1027. (b) Kivala, M.; Boudon, C.; Gisselbrecht, J.-P.; Seiler, P.;
Gross, M.; Diederich, F. Chem. Commun. 2007, 4731–4733.
(14) See the Supporting Information for ORTEP representation of cyclobutene
15.
(15) Banwell, M. G.; Lupton, D. W.; Ma, X.; Renner, J.; Sydnes, M. O.
Org. Lett. 2004, 6, 2741–2744.
(16) Aldrich Cat. No. 299634-1G: Furuta, T.; Kitamura, Y.; Hashimoto, A.;
Fujii, S.; Tanaka, K.; Kan, T. Org. Lett. 2007, 9, 183–186.
(17) See the Supporting Information for ORTEP representation of cyclobutene
25.
(18) Baldwin, J. E.; Leber, P. A. Org. Biomol. Chem. 2008, 6, 36–47.
J. Org. Chem. Vol. 73, No. 18, 2008 7307

Ashburn et al.
SCHEME 2. Proposed Mechanistic Pathway
ratio of biaryl to cyclooctatriene (1.8:1, 14:25) (entry c). Since
excluding light favored formation of the biaryl 14, the irradiation
with light might favor the cyclooctatriene 25.20 As was expected,
lowering the reaction temperature to 140 °C gave no reaction
as previously shown since none of cyclooctatriene 25 was
formed.21 Interestingly, exposure of cyclobutene 15 to a 120
W halogen bulb at the same temperature (140 °C) led to the
formation of the cyclooctatriaene 18 as the sole product in good
yield (83%) (entry e). It should be noted that variation of light
exposure on the initial reaction between acetylene 13 and diene
11 appeared to have no effect on the course of the reaction as
similar distributions (14:15) of products (ca. 1.3-1.5:1) were
found.
A proposed mechanistic pathway for the formation of these
products is shown in Scheme 2. The initial reaction at 140 °C
proceeds through at least two competing pathways (Paths A
and B). Path A involves a net [2+2] cycloaddition at the γ and
δ atoms of the diene 11 with the alkyne 13. While thermal [2+2]
cycloadditions are normally forbidden based on the Woodward-
Hoffmann rules,22 alkyne 13 does possess sets of orthogonally
disposed p orbitals, which could participate in a concerted [2+2]
pathway. The thermal [2+2] cycloadditions of ketenes are
thought to proceed through a similar pathway.23 The fact that
variation in exposure to light on the initial reaction between 11
and 13 has no impact on the product distribution does indirectly
support the concerted [2+2] pathway. Path B would proceed
through a normal [4+2] cycloaddition to yield the bicyclo[2.2.2]
octadiene 27, which rapidly extrudes ethylene to give biaryl
14. The rate of the [4+2] cycloreversion is thought to be driven,
in part, by the relief of steric compression (along with the
aromaticity produced in the new benzene ring in 14). Although
we did not isolate this bicycle 27, we have documented its
existence in previous work at lower temperatures.10b Upon
thermolysis of cyclobutene 15, a [1,3] sigmatropic carbon shift
of the γ, ꢀ bond would lead to the [2.2.2] bicycle 27. This
pathway could proceed via a concerted manifold or a diradical
intermediate. Support for at least a predominance of the
concerted [1,3] sigmatropic pathway can be found in the
observation that exclusion of light led to an augmentation of
the biaryl 14 (Table 1, entry c). Subsequent extrusion of ethylene
via the [4+2] cycloreversion reveals the biaryl 14. Alternatively,
photolysis of cyclobutene 15 would induce homolytic cleavage
of the γ, δ bond to form the diradical intermediate 29.
Subsequent spin flip and recombination would produce the triene
25. Thermal 4π electrocyclic opening of the cyclobutene 15 is
also a possibility as these reactions are thermally allowed;
however, this concerted pathway would produce a trans double
bond in the 8-membered ring. Support for the diradical or
stepwise process is found in the exclusive formation of
cyclooctatriene 25 under photolysis (Table 1, entry e).
In conclusion, the use of the electron deficient diene 11 in
the DAB strategy has led to the elucidation of a competing
[2+2] cycloaddition reaction to give a cyclobutene 15 along
with the normally observed [4+2] cycloaddition which leads
to biaryl 14. Heating of the cyclobutene 15 at elevated
temperature results in the formation of biaryl 14 via a [1,3]
sigmatropic carbon shift and a cyclooctatriene 25 resulting from
opening of the highly strained bicycle. Variation of heat and
light exposure led to changes in product distribution. On the
basis of the findings described within, an alternate mechanism
for biaryl formation in our DAB chemistry may be operable:
namely, an initial [2+2] cycloaddition followed by [1,3]
sigmatropic carbon shift. It is unclear at this juncture if this
competitive [2+2] cycloaddition/[1,3] shift pathway is only
accessible with electron deficient dienes such as 11 or is more
broadly applied to electron rich dienes. Further detailed studies
into the nature of our DAB strategy will be reported in due
course.
Experimental Section
Biaryl 14 and Cyclobutene 15. To a pressure vessel containing
acetylene 13 (105 mg, 0.564 mmol) was added diene 11 (234 mg,
1.69 mmol) and xylenes (1.1 mL) at rt. The mixture was heated at
140 °C for 6 h then allowed to cool to rt. The mixture was loaded
directly onto silica gel and purified by chromatography over silica
gel, eluting with 10% EtOAc/hexanes, and recrystallized from Et2O/
petroleum ether to give 14 (66.1 mg, 0.227 mmol, 40%) as a yellow
crystalline solid and bicyclo[4.2.0]octadiene 15 (52.8 mg, 0.166
mmol, 29%) as a yellow crystalline solid. Biaryl 14: Mp 72-73
(19) The molecular modelling program Spartan ‘06 was used to carry out
the Density Functional B3LYP calculations. The 6-31G** basis set was chosen
to perform the geometry optimization. Computations were performed with a
Linux workstation running Spartan version ‘06.
(20) Wender, P. A.; Leichleiter, J. C. J. Am. Chem. Soc. 1977, 99, 267–68.
(21) This result was also observed in the initial reaction of acetylene 13 and
diene 11 (Scheme 1).
(22) Woodward, R. B.; Hoffmann, R. J. Am. Chem. Soc. 1965, 87, 395–
397.
(23) (a) Tidwell, T. T. Eur. J. Org. Chem. 2006, 56, 3–576. (b) Holder, R. W.
J. Chem. Educ. 1976, 53, 81–85.
1
°C; IR (neat) 2958, 1722, 1528, 1350, 1264 cm-1; H NMR (400
MHz, CDCl3) δ 8.20 (dd, J ) 7.8, 1.4 Hz, 1H), 8.00 (dd, J ) 8.3,
7308 J. Org. Chem. Vol. 73, No. 18, 2008

Diels-Alder Approach to Biaryls
1.1 Hz, 1H), 7.75 (dd, J ) 8.0, 1.1 Hz, 1H), 7.65 (td, J ) 7.5, 1.4
Hz, 1H), 7.56 (td, J ) 7.8, 1.4 Hz, 1H), 7.51 (t, J ) 8.2 Hz, 1H),
7.19 (dd, J ) 7.6, 1.0 Hz, 1H), 3.76 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 166.2, 149.3, 136.6, 136.1, 135.4, 133.6, 132.6, 130.8,
129.7, 129.0, 128.7, 128.6, 122.5, 52.2; HRMS (CI+) calcd for
C14H11NO4Cl (M + H) 292.0377, found 292.0382. Cyclobutene
15: Mp 94-95 °C; IR (neat) 2928, 1711, 1532, 1435, 1368, 1250
hexanes, to give a mixture of two compounds as determined by
crude H NMR analysis that were consistent with biaryl 22 and
1
cyclobutene 23. To this mixture (0.358 mmol) was added Zn dust
(117 mg, 1.79 mmol) and AcOH (1.79 mmol) at rt. After 30 min,
the reaction was filtered over celite, eluting with EtOAc (20 mL).
The organic phase was basified with saturated aq NaHCO3 and
washed with H2O (15 mL) and saturated aq NaCl (15 mL). The
dried extract (MgSO4) was purified by chromatography over silica
gel, eluting with 0-50% EtOAc/CH2Cl2, to give 2415 (35.2 mg,
0.180 mmol, 51%) as a white crystalline solid. 1H NMR (400 MHz,
d6-DMSO) δ 11.7 (s, 1H), 8.52 (d, J ) 8.2 Hz, 1H), 8.40 (d, J )
7.8 Hz, 1H), 8.34 (dd, J ) 7.4, 1.3 Hz, 1H), 7.87 (td, J ) 7.2, 1.4
Hz, 1H), 7.66 (td, J ) 8.0, 1.1 Hz, 1H), 7.50 (td, J ) 8.3, 1.2 Hz,
1H), 7.38 (d, J ) 8.1, 1.0 Hz, 1H), 7.28 (td, J ) 8.2, 1.2 Hz, 1H);
13C NMR (100 MHz, d6-DMSO) δ 161.3, 137.0, 134.7, 133.3,
130.1, 128.4, 127.9, 126.2, 123.7, 123.1, 122.7, 118.0, 116.6.
Cyclooctatriene 25. To a pressure vessel containing cyclobutene
15 (16.9 mg, 0.0529 mmol) was added xylenes (0.2 mL). The
solution was irradiated (120 W halogen bulb) with heating at 140
°C. After 40 h, the solution was cooled to rt and loaded directly
onto silica gel. The reaction was purified by chromatography over
silica gel, eluting with 10-20% EtOAc/hexanes to give cyclooc-
tatriene 25 (14.0 mg, 0.0438 mmol, 83%) as a yellow solid. Mp
86-87 °C; IR (neat) 2952, 1711, 1532, 1434, 1357 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.77 (dd, J ) 8.2, 1.2 Hz, 1H), 7.67 (dd, J )
8.1, 1.3 Hz, 1H), 7.22 (d, J ) 4.8 Hz, 1H), 6.03 (dt, J ) 9.9, 5.0
Hz, 1H), 5.78-5.83 (m, 2H), 3.80 (s, 3H), 2.65-2.91 (m, 2H),
2.61-2.66 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 167.9, 150.6,
137.5, 136.4, 136.12, 136.11, 135.5, 135.3, 133.8, 128.8, 126.5,
124.9, 122.4, 52.0, 28.7, 25.7; HRMS (EI+) calcd for C16H14NO4Cl
(M+) 319.06113, found 319.06050.
Biaryl 14 and Cyclooctatriene 25. Procedure A.To a pressure
vessel was added cyclobutene 15 (174 mg, 0.544 mmol) and xylenes
(1.09 mL) and the solution was heated at 160 °C for 6 h. The
mixture was cooled to rt then purified by chromatography over silica
gel, eluting with 5-10% EtOAc/hexanes, to give biaryl 14 (66.8
mg, 0.229 mmol, 42%) and cyclooctatriene 25 (65.2 mg, 0.204
mmol, 37%) as yellow crystalline solids.
Procedure B. To a pressure vessel was added cyclobutene 15
(48.3 mg, 0.151 mmol) and xylenes (0.30 mL). After heating at
160 °C for 6 h in the absence of light, the mixture was cooled to
rt, loaded directly onto silica gel, and purified via silica gel
chromatography, eluting with 5-10% EtOAc/hexanes to give biaryl
14 (20.7 mg, 0.0709 mmol, 47%) and cyclooctatriene 25 (12.6 mg,
0.0393 mmol, 26%).
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.58 (dd, J ) 8.2, 1.2 Hz,
1H), 7.56 (dd, J ) 8.2, 1.2 Hz, 1H), 7.33 (t, J ) 8.1 Hz, 1H), 6.98
(dd, J ) 5.8, 2.8 Hz, 1H), 6.51 (s, 1H), 4.06 (ddd, J ) 5.6, 4.1, 1.4
Hz, 1H), 3.73 (s, 3H), 2.67-3.25 (m, 1H), 2.06-2.15 (m, 1H),
1.98-2.03 (m, 1H), 1.48 (dddd, J ) 12.3, 9.6, 5.4, 4.2 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 167.3, 150.5, 140.9, 137.7, 137.2,
135.1, 133.3, 133.28, 128.7, 127.0, 121.6, 51.7, 44.1, 39.7, 25.2,
20.8; HRMS (CI+) calcd for C16H15NO4Cl (M +H) 320.06896,
found 320.06881.
Biaryl 16. To a pressure vessel containing acetylene 13 (47.2
mg, 0.258 mmol) was added diene 5 (85.8 mg, 92.3 µL, 0.775
mmol) at rt. After heating at 140 °C for 2 h, the crude mixture was
cooled to rt and purified by chromatography over silica gel, eluting
with 10% EtOAc/hexanes to give biaryl 16 (56.0 mg, 0.212 mmol,
82%) as a crystalline solid. Mp 69-70 °C; IR (neat) 2944, 1530,
1
1358, 1261 cm-1; H NMR (400 MHz, CDCl3) δ 8.74 (dd, J )
8.2, 1.3 Hz, 1H), 7.73 (dd, J ) 8.0, 1.2 Hz, 1H), 7.45 (t, J ) 8.1
Hz, 1H), 7.44 (ddd, J ) 7.3, 6.4, 1.7 Hz, 1H), 7.19 (dd, J ) 7.5,
1.8 Hz, 1H), 7.07 (td, J ) 7.5, 1.0 Hz, 1H), 7.00 (dd, J ) 8.4, 1.0
Hz, 1H), 3.76 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 156.3, 151.1,
136.3, 133.6, 132.1, 130.4, 130.2, 128.7, 123.3, 122.3, 120.7, 111.0,
55.6; HRMS (CI+) calcd for C13H10NO3Cl (M + H) 263.03492,
found 263.03508.
Biaryl 19 and Cyclobutene 20. To a pressure vessel containing
acetylene 18 (61.7 mg, 0.273 mmol) was added diene 11 (113 mg,
0.819 mmol) and xylenes (0.55 mL). After heating at 140 °C for
6 h, the mixture was cooled to rt, loaded directly onto silica gel,
and purified via silica gel chromatography, eluting with 75-100%
hexanes/PhMe to give biaryl 19 (33.0 mg, 0.0981 mmol, 36%) as
a yellow oil and cyclobutene 20 (26.8 mg, 0.0737 mmol, 27%) as
a yellow oil. Biaryl 19: IR (neat) 2952, 1723, 1528, 1434, 1350,
1
1265 cm-1; H NMR (400 MHz, CDCl3) δ 8.19 (dd, J ) 7.8, 1.3
Hz, 1H), 8.03 (dd, J ) 8.2, 1.2 Hz, 1H), 7.93 (dd, J ) 8.0, 1.0 Hz,
1H), 7.64 (td, J ) 7.6, 1.4 Hz, 1H), 7.56 (td, J ) 7.8, 1.4 Hz, 1H),
7.42 (t, J ) 8.2 Hz, 1H), 7.16 (dd, J ) 7.6, 1.2 Hz, 1H), 3.75 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 166.1, 149.2, 138.6, 137.8,
136.8, 132.6, 130.8, 129.7, 129.2, 128.9, 128.7, 125.5, 123.1, 52.2;
HRMS (EI+) calcd for C14H10NO4Br (M+) 334.97931, found
334.97775. Cyclobutene 20: IR (neat) 2919, 1716, 1525, 1438,
Acknowledgment. Financial support was provided by the
National Science Foundation (CHE-0549884). The authors
would like to thank Professor Max Deinzer (OSU) and Dr. Jeff
Morre´ (OSU) for mass spectra data and Michael R. Naffziger
(OSU) and Dr. Roger Hanselmann (Rib-X Pharmaceuticals) for
their helpful discussions..
1
1371, 1248 cm-1; H NMR (400 MHz, CDCl3) δ 7.79 (dd, J )
8.0, 1.0 Hz, 1H), 7.61 (dd, J ) 8.1, 1.1 Hz, 1H), 7.26 (t, J ) 8.0
Hz, 1H), 6.97 (dd, J ) 5.8, 2.8 Hz, 1H), 6.48 (s, 1H), 4.08 (t, J )
4.0 Hz, 1H), 3.73 (s, 3H), 3.23 (s, 1H), 2.69 (d, J ) 16 Hz, 1H),
2.09-2.18 (m, 1H), 1.97-2.03 (m, 1H), 1.44-1.51 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 167.4, 150.5, 140.7, 138.9, 137.6, 136.6,
133.3, 129.2, 129.0, 124.6, 122.2, 51.7, 44.2, 39.5, 25.2, 20.9;
HRMS (EI+) calcd for C16H14NO4Br (M + Na) 386.0004, found
386.0009.
Supporting Information Available: 1H and 13C spectra for
all new compounds and X-ray crystallographic data for com-
pounds 15 (CCDC 686300) and 25 (CCDC 686299). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Lactam 24. To a pressure vessel containing acetylene 21 (52.6
mg, 0.358 mmol) was added diene 11 (148 mg, 1.07 mmol) at rt.
The mixture was heated at 140 °C for 6 h then allowed to cool to
rt. The crude mixture was loaded directly on silica gel and purified
by chromatography over silica gel, eluting with 10% EtOAc/
JO801245A
J. Org. Chem. Vol. 73, No. 18, 2008 7309