Straightforward access to the [3.2.2]nonatriene structural framework via intramolecular cyclopropenation/buchner reaction/cope rearrangement cascade

Article abstract of DOI:10.1021/ol503498n

A one-pot cascade process of benzyl enoldiazoacatates, initiated by dirhodium(II)-catalyzed intramolecular cyclopropene formation, occurs via a subsequent Buchner reaction and Cope rearrangement to provide straightforward access to bicyclo[3.2.2]nonatriene derivatives in high yields and selectivities.

Full text of DOI:10.1021/ol503498n

Letter
pubs.acs.org/OrgLett
Straightforward Access to the [3.2.2]Nonatriene Structural
Framework via Intramolecular Cyclopropenation/Buchner Reaction/
Cope Rearrangement Cascade
Xinfang Xu,*,†,‡ Xiangbo Wang,† Peter Y. Zavalij,‡ and Michael P. Doyle*,‡
†Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, China
‡Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States
S
* Supporting Information
ABSTRACT: A one-pot cascade process of benzyl enoldiazoacatates, initiated by dirhodium(II)-catalyzed intramolecular
cyclopropene formation, occurs via a subsequent Buchner reaction and Cope rearrangement to provide straightforward access to
bicyclo[3.2.2]nonatriene derivatives in high yields and selectivities.
he Buchner reaction, a two-step C−C bond-forming
Intramolecular Buchner reactions performed with diazoke-
tones and diazoacetamides are common,2−7 but we are aware of
only three reports using diazoacetates and none with enol
diazoacetates.8 In an effort to determine if the Buchner reaction
from reactions with diazoacetates could be developed for
subsequent electrocyclic processes, we have chosen to examine
catalytic reactions of benzyl enol diazoacetates.9 The positioning
of the vinyl groups in the norcaradiene structure from
intramolecular aromatic cycloaddition with the vinyl group
from the silylated enol substituent provides a structural
framework that is suitable for a subsequent Cope rearrangement
which could form either or both of two bicyclic products
(Scheme 2). We now report a straightforward and highly
selective access to one of these bicyclononatriene derivatives via a
dirhodium-catalyzed intramolecular cascade process that was
initiated from readily accessible enol diazoacetates.
T
reaction between aromatic hydrocarbons and carbene
species1 that is an important method for the preparation of
seven-membered ring compounds, has been successfully applied
to the total synthesis of natural products.2 In this transformation,
carbene addition to the aromatic ring forms a norcaradiene
structure3 that exists in equilibrium with its valence tautomeric
cycloheptatriene structure, with the latter usually being the more
stable (Scheme 1).4b,5 Dirhodium catalysts have proven to be
Scheme 1. Intramolecular Buchner Reaction
Rapid and quantitative conversion of benzyl enol diazoacetate
1a to the corresponding donor−acceptor cyclopropene was
observed when 1a was treated with a catalytic amount of rhodium
acetate at room temperature. The intermediate formation of
donor−acceptor cyclopropenes from enol diazoacetates in
dirhodium(II) catalyzed reactions, and their possible role as
reactive metal carbene precursors, has recently been estab-
lished.10 However, once formed, only relatively slow decom-
superior to those of copper for the Buchner reaction,5 but
recently introduced ruthenium catalysts also show potential.6
Intramolecular reactions of diazo ketones and diazoacetamides
have been examined to elucidate structural influences of the diazo
compound on selectivity (e.g., aromatic cycloaddition vs
substitution vs C−H insertion),2,7 and dirhodium ligand
influences on reactivity and selectivity have shown that
electron-withdrawing ligands favor aromatic cycloaddition.4
Received: December 4, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol503498n
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Letter
Scheme 2. Aromatic Cycloaddition/Cope Rearrangement
Cascade to Bicyclononatrienes
position of this cyclopropene was observed in a broad survey that
examined a range of temperatures (0−60 °C) with dirhodium
catalysts, including Rh2(tfa)4 and Rh2(pfb)4, that favor aromatic
Figure 2. X-ray crystal structures of 2b and 3b.
7
1
structures are rare,14 especially for those with diverse functional
groups.
cycloaddition over C−H insertion. Figure 1 describes the H
The influence of substituents was investigated with various
electron-rich benzyl enol diazoacetates (Scheme 3). Reactions
Scheme 3. Applications of Aromatic Cycloaddition/Cope
Rearrangement
Figure 1. Sequential conversion of enol diazoacetate 1b to donor−
acceptor cyclopropene to aromatic cycloaddition product 2b then to
Cope rearrangement product 3b.
NMR spectral monitored course of the reaction with 1b
catalyzed by Rh2(OAc)4, whose electron-rich p-methoxybenzyl
group is conducive toward aromatic cycloaddition.
At room temperature in CDCl3, 1b undergoes dinitrogen
extrusion and rearrangement to the donor−acceptor cyclo-
propene rapidly with no evidence of further reaction during the
first 5 min. At 40 °C within 1 h (or at room temperature in over 5
h), cyclopropene is converted to the aromatic cycloaddition
product 2b exclusively, and this product is stable at these low
temperatures. However, heating the reaction solution in the
sealed vessel overnight causes formation of the structurally
symmetric bicyclo[3.2.2]nona-2,6,8-triene product 3b by Cope
rearrangement (Scheme 2, path A) as the only product in 80%
isolated yield. Control reactions showed that the dirhodium
catalyst is essential for the Buchner reaction from reaction with
both the enol diazoacetate and the corresponding donor−
acceptor cyclopropene.
The structures of bicyclo[5.3.0]nonatriene 2b and
bicyclo[3.2.2]nonatriene 3b were confirmed by single-crystal
X-ray diffraction analysis (Figure 2).11 Bicyclo[3.2.2]nona-2,6,8-
trienes have unique structural frameworks that have attracted
synthetic and theoretical interest,12 and they have recently been
found to be a core unit in some polycyclic bioactive natural
compounds.13 However, synthetic methods used to access these
a
Reactions were carried out on a 0.5 mmol scale in 2.0 mL of DCE
b
with 2.0 mol % of Rh2(OAc)4. The Cope rearrangement was carried
out at 40 °C instead of 70 °C, and the reaction was complete in 5 h.
c
The Cope rearrangement was carried out at 80 °C instead of 70 °C,
and the reaction was complete in 24 h.
were initiated with Rh2(OAc)4 in 1,2-dichloroethane at room
temperature which caused a rapid loss of dinitrogen and
generation of the corresponding donor−acceptor cyclopropene
within 5 min. Warming to 40 °C caused aromatic cycloaddition
in 1 h, and then continued heating at 70 °C overnight converted
the Buchner reaction product 2 to 3 via the Cope rearrangement.
All of the reactant diazo compounds with electron-donating
benzyl ester substituents gave bicyclo[3.2.2]nona-2,6,8-triene
products from aromatic cycloaddition/Cope rearrangement in
B
DOI: 10.1021/ol503498n
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Letter
high yield (60−88% yield). Those enol diazoacetates without
electron-donating alkoxy substituents also formed their corre-
sponding donor−acceptor cyclopropenes rapidly but on
warming to higher temperatures underwent slow decomposition
to product mixtures that were not further analyzed. 1-Naphthyl
and 3,4-(methylenedioxy)benzyl esters generated the corre-
sponding bicyclo[3.2.2]nonatrienes 3c and 3d in 65% and 72%
yield, respectively. Substrates with two electronic donating
groups were more reactive compared to those with one alkoxy
substituent, and their reactions formed Cope rearrangement
products 3e−g in greater than 81% yield at 40 °C. Enol
diazoacetates with substitutents at the vinylogous position (R1 =
Me, Et, and Ph) were also examined, and they smoothly
generated the Cope rearrangement products in high yield 3h−j,
although higher temperatures and longer reaction times were
necessary for the phenyl-substituted enol diazoacetate 1j. It
should be noted that high diastereoselectivity was observed for
product 3i, and its relative structure was confirmed by 1D NOE
analysis, in which the ethyl group and the 3-methoxy group of the
original aryl ring are on opposite sides.
were more reactive toward aromatic cycloaddition than was
Rh2(OAc)4.
Examination of substrates from Scheme 3 under optimized
conditions from Table 1 showed that several of the substrates
(1c, 1e, and 1g) are directly converted to the final Cope
rearrangement products 3 at room temperature with moderate
enantioselectivity and high yield (Scheme 4).16 Even at 0 °C, 1e
a
Scheme 4. Catalytic Asymmetric Synthesis of 2 and 3
Attempts to perform these reactions with enantiocontrol were
made with initial attention given to the aromatic cycloaddition
process. Previous reports of asymmetric induction in the
Buchner reaction with diverse chiral catalysts have shown
optimum enantiocontrol in the general range of 56−81% ee.8c,15
Key results from our survey with 1b are reported in Table 1. The
Table 1. Determination of Optimum Reaction Conditions for
a
Asymmetric Catalysis in Aromatic Cycloaddition
a
Reactions were carried out on a 0.2 mmol scale in 1.0 mL of solvent
with 2.0 mol % of Rh2(S-PTTL)4.
gave bicyclo[3.2.2]nona-2,6,8-triene 3e in 83% yield with 67%
ee. The Buchner reaction products 2b and 2h were isolated as
only products from their corresponding enol diazoacetates at
room temperature, both in high yield and with 69% ee and 77%
ee, respectively. However, loss of the enantiomeric excess was
observed during the process leading to the Cope rearrangement
of 2h to form 3h, either with or without dirhodium catalyst at 60
°C ; enantiomeric excess decreased from 71% ee for 2h to 41%
(with catalyst) and 25% (without catalyst) for 3h. This was the
result of epimerization of the newly formed chiral center in the
intermediate norcaradiene at the higher temperature used for the
Cope rearrangement, and this equilibrium with a stabilized ylide
was facilitated by the methoxy group in the para position of the
original aryl ring (Scheme 5). Moody and co-workers reported a
similar epimerization for loss of diastereoselection in a Buchner
reaction of a p-methoxybenzyl diazomalonate ester.4b The same
phenomenon was also observed during the formation of 2j and 3j
under standard reaction conditions. Although 2j and 3j were
obtained in 1:1 ratio with 75% ee and 82% ee, respectively, slow
b
c
entry
Rh(II)
solvent
yield (%) ee (%)
1
Rh2(S-PTA)4
Rh2(S-PTPA)4
Rh2(S-PTL)4
DCM
DCM
DCM
DCM
DCM
DCE
80
75
72
82
75
80
75
65
80
81
85
76
81
30
29
48
51
6
2
3
4
Rh2(S-PTTL)4
Rh2(S-DOSP)4
Rh2(S-PTTL)4
Rh2(S-PTTL)4
Rh2(S-PTTL)4
Rh2(S-PTTL)4
Rh2(S-PTTL)4
Rh2(S-PTTL)4
Rh2(S-PTTL)4
Rh2(S-PTAD)4
5
6
44
60
45
54
53
45
69
65
7
n-heptane
8
chloroform
9
fluorobenzene
chlorobenzene
toluene
10
11
12
13
α,α,α-trifluorotoluene
α,α,α-trifluorotoluene
a
Reactions were conducted by adding 1b (0.2 mmol) in 1.0 mL of the
solvent to the solution of catalyst in 0.5 mL of the solvent via syringe
pump over 30 min. Isolated yield. The enantioselectivity was
determined by chiral HPLC analysis: IB-3 column, 254 nm, 0.7 mL/
min, hexanes:IPA = 95:5, tR = 7.5, 8.4 min.
b
c
Scheme 5. Loss of Enantioselectivity Due to Zwitterionic
Intermediate
more sterically encumbered catalysts provided higher selectiv-
ities, and Hashimoto’s sterically bulky dirhodium carboxylate
catalyst Rh2(S-PTTL)4 (entry 13) was optimum for enantiocon-
trol among those that were investigated. Solvent influenced
enantioselectivity with α,α,α-trifluorotoluene being the optimum
solvent for this transformation. The chiral dirhodium catalysts
C
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Organic Letters
Letter
(7) (a) Padwa, A.; Austin, D. J.; Hornbuckle, S. F.; Semones, M. A.;
Doyle, M. P.; Protopopova, M. N. J. Am. Chem. Soc. 1992, 114, 1874.
(b) Padwa, A.; Austin, D. J.; Price, A. T.; Semones, M. A.; Doyle, M. P.;
Protopopova, M. N.; Winchester, W. R.; Tran, A. J. Am. Chem. Soc. 1993,
115, 8669.
(8) (a) Doyle, M. P.; Dyatkin, A. B.; Autry, C. L. J. Chem. Soc., Perkin
Trans.1 1995, 619. (b) Doyle, M. P.; Protopopova, M. N.; Peterson, C.
S.; Vitale, J. P.; McKervey, M. A.; Garcia, C. F. J. Am. Chem. Soc. 1996,
118, 7865. (c) Doyle, M. P.; Ene, D. G.; Forbes, D. C.; Pillow, T. H. J.
Chem. Soc., Chem. Commun. 1999, 1691.
(9) For recent reviews of research with enol diazoacetates: (a) Xu, X.;
Doyle, M. P. Acc. Chem. Res. 2014, 47, 1396. (b) Xu, X.; Doyle, M. P.
Aust. J. Chem. 2014, 67, 365.
(10) (a) Xu, X.; Zavalij, P. Y.; Doyle, M. P. Chem. Commun. 2013, 49,
10287. (b) Xu, X.; Zavalij, P. Y.; Doyle, M. P. J. Am. Chem. Soc. 2013,
135, 12439. (c) Archambeau, A.; Miege, F.; Meyer, C.; Cossy, J. Angew.
Chem., Int. Ed. 2012, 51, 11540. (d) Miege, F.; Meyer, C.; Cossy, J.
Angew. Chem., Int. Ed. 2011, 50, 5932. (e) Miege, F.; Meyer, C.; Cossy, J.
Org. Lett. 2010, 12, 4144.
racemization of 2j occurred either with or without Rh2(S-
PTTL)4 at room temperature, and total loss of optical purity for
2j was observed after just 3 days at room temperature; on the
other hand, no loss in enantioselectivity for 3j was observed even
after heating in DCE at 80 °C for a few hours.
In conclusion, we have developed a straightforward access to
bicyclo[5.3.0]- and bicyclo[3.2.2]nonatriene derivatives in high
yields and selectivities. This one-pot cascade intramolecular
transformation was initiated by dirhodium-catalyzed donor−
acceptor cyclopropene formation from corresponding enol
diazoacetates, followed by the dirhodium-catalyzed Buchner
reaction and subsequent Cope rearrangement by gradually
increasing the reaction temperature and without the use of
additional catalyst(s). Further studies exploring the scope and
development new transformations by interception of active
intermediates/products during metal carbene reactions, includ-
ing asymmetric catalysis, are underway.
(11) CCDC 1010091 contains the supplementary crystallographic
data for 2b, and CCDC 1010092 contains the supplementary
crystallographic data for 3b. These data can be obtained free of charge
from the Cambridge crystallographic data centre via www.ccdc.cam.ac.
uk/data_request/cif.
(12) (a) Grutzner, J. B.; Winstein, S. J. Am. Chem. Soc. 1972, 94, 2200.
(b) Moncur, M. V.; Grutzner, J. B. J. Am. Chem. Soc. 1973, 95, 6451.
(c) Yamabe, S.; Minato, T.; Watanabe, T.; Machiguchi, T. Theor. Chem.
ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures and characterization data of
the products. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Authors
Acc. 2011, 130, 981. (d) Blumel, J.; Kohler, F. H. Chern. Ber. 1993, 126,
̈
■
1283.
(13) (a) Kramer, C. S.; Nieger, M.; Brase, S. Eur. J. Org. Chem. 2014,
̈
*E-mail: xinfangxu@suda.edu.cn.
*E-mail: mdoyle3@umd.edu.
Notes
2150. (b) Snyder, S. A.; Breazzano, S. P.; Ross, A. G.; Lin, Y.; Zografos,
A. L. J. Am. Chem. Soc. 2009, 131, 1753. (c) Li, Y.; Shibahara, A.; Matsuo,
Y.; Tanaka, T.; Kouno, I. J. Nat. Prod. 2010, 73, 33.
(14) Recent reports: (a) Moerdyk, J. P.; Bielawski, C. W. J. Am. Chem.
The authors declare no competing financial interest.
Soc. 2012, 134, 6116. (b) Carreco̧ , M. C.; Ortega-Guerra, M.; Ribagorda,
M.; Sanz-Cuesta, M. J. Chem.Eur. J. 2008, 14, 621. (c) Thangaraj, M.;
Bhojgude, S. S.; Bisht, R. H.; Gonnade, R. G.; Biju, A. T. J. Org. Chem.
2014, 79, 4757.
ACKNOWLEDGMENTS
■
Support to M.P.D. from the National Institutes of Health (GM
46503) and from the National Science Foundation (CHE-
1212446) is gratefully acknowledged. X.F.X. acknowledges the
startup funding from Soochow University and Key Laboratory of
Organic Synthesis of Jiangsu Province.
(15) (a) Kennedy, M.; McKervey, M. A.; Maguire, A. R.; Roos, G. H. P.
J. Chem. Soc., Chem. Commun. 1990, 361. (b) Doyle, M. P.; Davies, S. B.;
Hu, W. J. Chem. Soc., Chem. Commun. 2000, 867. (c) O’Keeffe, S.;
Harrington, F.; Maguire, A. R. Synlett. 2007, 2367. (d) Slattery, C. N.;
Clarke, L.-A.; O’Neill, S.; Ring, A.; Ford, I.; Maguire, A. R. Synlett. 2012,
765.
REFERENCES
■
(16) For a thorough study of reactivity and selectivity in Cope
rearrangement see: Rhoads, S. J.; Raulins, N. R. Org. React. 2011, 22, 1.
(1) (a) Buchner, E.; Curtius, T. Ber. Dtsch. Chem. Ges 1885, 2377.
(b) Doering, W. V. E.; Laber, G.; Vonderwahl, R.; Chamberlain, N. F.;
Williams, R. B. J. Am. Chem. Soc. 1956, 78, 5448.
(2) (a) Sugimura, T.; Sato, Y.; Im, C. Y.; Okuyama, T. Org. Lett. 2004,
6, 4439. (b) Kennedy, M.; McKervey, M. A. J. Chem. Soc., Perkin Trans. 1
1991, 10, 2565. (c) Nani, R. R.; Reisman, S. E. J. Am. Chem. Soc. 2013,
135, 7304. (d) McDowell, P. A.; Foley, D. A.; O’Leary, P.; Ford, A.;
Maguire, A. R. J. Org. Chem. 2012, 77, 2035. (e) Frey, B.; Wells, A. P.;
Rogers, D. H.; Mander, L. N. J. Am. Chem. Soc. 1998, 120, 1914.
(3) (a) Brawn, R. A.; Zhu, K.; Panek, J. S. Org. Lett. 2014, 16, 74.
(b) Manitto, P.; Monti, D.; Speranza, G. J. Org. Chem. 1995, 60, 484.
(4) (a) Doyle, M. P.; Shanklin, M. S.; Oon, S. M.; Pho, H. Q.;
Vanderheide, F. R.; Veal, W. R. J. Org. Chem. 1988, 53, 3384. (b) Moody,
C. J.; Miah, S.; Slawin, A. M. Z.; Mansfield, D. J.; Richards, I. C. J. Chem.
Soc., Perkin Trans. 1 1998, 17, 4067. (c) Kennedy, M.; McKervey, M. A.;
Maguire, A. R.; Tuladhar, S. M.; Twohig, M. F. J. Chem. Soc., Perkin
Trans. 1 1990, 10, 1047. (d) Maguire, A. R.; Buckley, N. R.; O’Leary, P.;
Ferguson, G. J. Chem. Soc., Perkin Trans. 1 1998, 17, 4077. (e) McDowell,
P. A.; Foley, D. A.; O’Leary, P.; Ford, A.; Maguire, A. R. J. Org. Chem.
2012, 77, 2035. (f) Saba, A. Tetrahedron Lett. 1990, 31, 4657.
(5) Doyle, M. P., McKervey, M. A.; Ye, T. Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds; John Wiley & Sons, Inc.: New
York, 1998; Chapter 6.
(6) Lo, V. K. Y.; Guo, Z.; Choi, M. K. W.; Yu, W. Y.; Huang, J. S.; Che,
C. M. J. Am. Chem. Soc. 2012, 134, 7588.
D
DOI: 10.1021/ol503498n
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