One-pot synthesis of bicyclic β-alkoxy amides from cyanohydrin ethers

Article abstract of DOI:10.1021/ol8000409

In this manuscript we report that Intramolecular Friedel-Crafts alkylation reactions of aryl-substituted a-alkoxy acylimines proceed in the presence of mild Lewis acids to afford bicyclic β-alkoxy amides. The intermediate acylimines are prepared through c

Full text of DOI:10.1021/ol8000409

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1139-1142
One-Pot Synthesis of Bicyclic
Amides from Cyanohydrin Ethers
â-Alkoxy
Qing Xiao and Paul E. Floreancig*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
florean@pitt.edu
Received January 8, 2008
ABSTRACT
In this manuscript we report that intramolecular Friedel−Crafts alkylation reactions of aryl-substituted
r-alkoxy acylimines proceed in the
presence of mild Lewis acids to afford bicyclic
â
-alkoxy amides. The intermediate acylimines are prepared through cyanohydrin ether
hydrozirconation and acylation of the resulting metalloimine, providing an operationally facile one pot protocol. A two-step variant of the
procedure has also been developed to effect cyclizations from acylimines that undergo competitive tautomerization.
An important objective in developing projects for diversity
oriented synthesis1 is to devise new molecular scaffolds that
uniquely orient functional groups in chemical space.2 Reac-
tions that rapidly increase the complexity of readily available
precursors through ring formation or stereocenter introduction
are quite useful for achieving this objective. We have initiated
a program that exploits the capacity of electrophilic acylimines
to react with a range of nucleophiles in the preparation of
structurally diverse libraries of amides.3 The acylimines are
derived from easily accessible nitriles through a sequence
of hydrozirconation and acylation.4 While our previous
efforts have been directed toward bimolecular nucleophilic
additions that form carbon-heteroatom bonds, we envisioned
that this process could also be applied to intramolecular
nucleophilic additions that produce carbocyclic structures in
a single operation (Scheme 1). In this manuscript we report
Scheme 1. Annulation through Nitrile Hydrozirconation,
Acylation, and Friedel-Crafts Alkylation
that nitrile-derived acylimines5 engage in Lewis acid-
mediated Friedel-Crafts alkylation reactions6 to form indanyl
or tetrahydronaphthyl amides. Employing cyanohydrin ether
(1) (a) Schreiber, S. L. Science 2000, 287, 1964. (b) Burke, M. D.;
Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46. (c) Spring, D. R.
Chem. Soc. ReV. 2005, 34, 472. (d) Tan, D. S. Nat. Chem. Biol. 2005, 1,
74. (e) Arya, P.; Joseph, R.; Gan, Z.; Rakic, B. Chem. Biol. 2005, 12, 163.
(2) Recent examples: (a) Brummond, K. M.; Mitasev, B. Org. Lett. 2004,
6, 2245. (b) Chen, C.; Li, X.; Neumann, C. S.; Lo, M. M.-C.; Schreiber, S.
L. Angew. Chem., Int. Ed. 2005, 44, 2249. (c) Stevens, B. D.; Nelson, S.
G. J. Org. Chem. 2005, 70, 4375. (d) Wipf, P.; Walczak, M. A. A. Angew.
Chem., Int. Ed. 2006, 45, 4172. (e) Mitasev, B.; Yan, B.; Brummond, K.
M. Heterocycles 2006, 70, 367. (f) Dandapani, S.; Duduta, M.; Panek, J.
S.; Porco, J. A., Jr. Org. Lett. 2007, 9, 3849. (g) Sunderhaus, J. D.;
Dockendorff, C.; Martin, S. F. Org. Lett. 2007, 9, 4223. (h) Ng, P. Y.;
Tang, Y.; Knosp, W. M.; Stadler, H. S.; Shaw, J. T. Angew. Chem., Int.
Ed. 2007, 46, 5352. (i) Luo, T.; Schreiber, S. L. Angew. Chem., Int. Ed.
2007, 46, 8250. (j) Su, S.; Porco, J. A., Jr. Org. Lett. 2007, 9, 4983.
(3) Wan, S.; Green, M. E.; Park, J.-H.; Floreancig, P. E. Org. Lett. 2007,
9, 5385.
(5) For reviews of acylimines and related species, see: (a) Petrini, M.;
Torregiani, E. Synthesis 2007, 159. (b) Maryanoff, B. E.; Zhang, H.-C.;
Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. ReV. 2004, 104, 1431.
(c) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817.
(6) For recent examples of intermolecular Friedel-Crafts reactions with
acylimines and related species, see: (a) Uraguchi, D.; Sorimachi, K.; Terada,
M. J. Am. Chem. Soc. 2004, 126, 11804. (b) Wang, Y.-Q.; Song, J.; Hong,
R.; Li, H.; Deng, L. J. Am. Chem. Soc. 2006, 128, 8156. (c) Ballini, R.;
Palmieri, A.; Petrini, M.; Torregiani, E. Org. Lett. 2006, 8, 4093. (d) Terada,
M.; Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 292. (e) Kang, Q.; Zhao,
Z.-A.; You, S.-L. J. Am. Chem. Soc. 2007, 129, 1484. (f) Rowland, G. B.;
Rowland, E. B.; Liang, Y.; Perman, J. A.; Antilla, J. C. Org. Lett. 2007, 9,
2609. (g) Tussetschla¨ger, S.; Baro, A.; Laschat, S.; Frey, W. Eur. J. Org.
Chem. 2007, 5590.
(4) Maraval, A.; Igau, A.; Donnadieu, B.; Majoral, J. P. Eur. J. Org.
Chem. 2003, 385.
10.1021/ol8000409 CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/16/2008

substrates leads to the formation of bicyclic â-alkoxy amides
with good to excellent levels of diastereocontrol. We also
report a two step variation of this method that can be applied
to acylimines that undergo tautomerization faster than
nucleophilic addition in the one-step protocol.
To test the viability of this protocol, we prepared nitrile 1
and subjected it to hydrozirconation, acylation with isobu-
tyroyl chloride, and activation with ZnCl2 (Scheme 2). This
that was prepared from commercially available trans-1-
amino-2-indanol. This stereochemical outcome is consistent
with cyclization through conformer 6 rather than chelated
conformer 5. This outcome can also be explained through
the methoxy and acylimine groups adapting pseudoaxial
orientations in the transition state (not shown).7 The trans-
diaxial geometry in the transition state would be consistent
with the Cornforth model,8 which has generated a revived
interest.9 The surprising preference for reaction through the
nonchelated structure10 can be rationalized by the untoward
1
steric interactions in 5. Notably, as indicated by H-1H
Scheme 2. Annulation through Nitrile Hydrozirconation and
coupling constants, the amido and alkoxy groups in 4 are
aligned in pseudoaxial orientations to alleviate allylic strain.
Cyclization reactions that yield tetrahydronaphthyl amides
proceed much more readily than those that form indanyl
amides. As shown in Scheme 4, nitrile 7, which contains an
Acylation
Scheme 4. Tetrahydronaphthyl Amide Preparation
reaction provided indanyl amide 2 in 78% yield. Optimal
yields were observed when CH2Cl2 was employed as the
solvent, and the activating methoxy group and Lewis acid
were required to promote cyclization.
Nitrile 3, which lacks the geminal methyl groups that
facilitate cyclization through the gem-dialkyl effect, was
subjected to the sequence (Scheme 3) to provide â-alkoxy
Scheme 3. Cyclization of a Cyanohydrin Ether and Product
Conformation
electron rich arene nucleophile, reacts instantaneously in the
presence of ZnCl2 and can cyclize in the absence of a Lewis
acid, albeit less efficiently. Arenes that lack an electron
dontating group at the para-position, such as 9, can be used
as nucleophiles with ZnCl2 acylimine activation. The ster-
eochemical outcomes in these reactions is critically depend-
ent upon the cyclization rate. Rapid cyclizations proceed
through the sterically favored conformation 11. Slower
cyclizations occur through Cram chelate-like conformer 12.
While chelation is disfavored in the construction of indanyl
(7) We thank an anonymous referee for bringing this possibility to our
attention.
(8) Cornforth, J. W.; Cornforth, R. H.; Mathew, K. K. J. Chem. Soc.
1959, 112.
amide 4 in 78% yield and with nearly complete diastereo-
control. The trans-orientation of the amido group and the
methoxy group were confirmed through NOESY studies (key
cross-peaks are shown in Scheme 3) and through coupling
constant and chemical shift analogy with a related structure
(9) (a) Evans, D. A.; Siska, S. J.; Cee, V. J. Angew. Chem., Int. Ed.
2003, 42, 1761. (b) Marco, J. A.; Carda, M.; D´ıaz-Oltra, S.; Murga, J.;
Falomir, E.; Roeper, H. J. Org. Chem. 2003, 68, 8577. (c) Cee, V. J.;
Cramer, C. J.; Evans, D. A. J. Am. Chem. Soc. 2006, 128, 2920.
(10) Activation by Lewis acid coordination to the nitrogen of the
acylimine in 6 is also reasonable.
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Org. Lett., Vol. 10, No. 6, 2008

amides, the higher homologs react smoothly because the
additional methylene group eliminates the steric interations
that are present in conformer 5.
Further studies on the scope of the process are summarized
in Table 1. Oxygen-containing (entries 1 and 5) and
alkoxy group variation in library syntheses. The diminished
stereoselectivity that results from the use of a benzyl ether
rather than a methyl ether is consistent with Keck’s observa-
tions11 that benzyl ethers are less likely than methyl ethers
to engage in chelation. A silylated phenol can be used as
the nucleophilic group (entry 8). Given the capacity to
convert aryl silyl ethers to aryl triflates and the versatility
of aryl triflates in transition metal-mediated bond-forming
processes,12 this substrate class is well-suited for further
library development.
Table 1. Scope of the Annulation Reactiona
Nitriles that do not have a substituent at the R-position
are poor substrates for the process, as observed in the
attempted conversion of 25 to 26 (Scheme 5). This can be
Scheme 5. Cyclization through a Two-Step Protocol
a Representative procedure: Cp2Zr(H)Cl (1.2 equiv) is added to a solution
of the nitrile (1 eq) in CH2Cl2. After stirring for 10 min at rt, the electrophile
(1.5 equiv) and ZnCl2 (1.5 equiv) are added and the mixture stirs for several
hours. See the Supporting Information for details.
attributed to the intermediate acylimine undergoing tau-
tomerization and subsequent decomposition faster than
nucleophilic addition under these reaction conditions. To
promote cyclization reactions from nitriles that lack substitu-
tion at the R-position, we devised a two-step variant of the
method. In this sequence, the nitrile is converted to a stable,
isolable acyl aminal through our recently reported method3
unsaturated (entries 2 and 6) acid chlorides are tolerated in
the scheme. Sulfonyl indoles are suitable nucleophiles for
the reaction (entry 3), demonstrating that the scope of
products that are available through the protocol includes
electron rich heterocyclic structures. Functionalized arenes
can engage in the chelation-promoted tetrahydronaphthyl
amide formation when the group is meta to the forming bond
(entries 4-6 and 8). Cyanohydrin benzyl ethers are effective
substrates (entry 7), thereby demonstrating the capacity for
(11) (a) Keck, G. E.; Castellino, S.; Wiley, M. R. J. Org. Chem. 1986,
51, 5478. (b) Keck, G. E.; Wager, C. A. Org. Lett. 2000, 2, 2307.
(12) Ritter, K. Synthesis 1993, 735.
Org. Lett., Vol. 10, No. 6, 2008
1141

in which MeOH acylimine addition proceeds faster than
decomposition. The acyl aminal is then ionized to form an
acyliminium ion by treatment with TMSOTf, in accord with
Kobayashi’s studies.13 Through this sequence, nitrile 25 was
converted to acyl aminal 27. Exposing 27 to TMSOTf led
to the formation of acyliminium ion 28 and cyclization to
yield indanyl amide 26 in 89% yield. This method is also
effective for promoting cyclizations from acyl aminals that
are accessed from cyanohydrin ethers, with indanyl amides
13 and 14 being formed in >90% yields from acyl aminals
29 and 30. These reactions proceed with somewhat higher
diastereocontrol than those that utilize the one-pot protocol.
A final noteworthy issue in this study concerns the relative
cyclization rates in the formation of the indanyl and
tetrahydronaphthyl ring systems. From the perspective of the
acylimine addition, these processes are 5-exo-trig and 6-exo-
trig cyclizations,14 repectively. Therefore, the substantially
faster cyclization to form the tetrahydronaphthyl system
appears to be somewhat unexpected. However, from the
perspective of the arene, initial cyclization step (Scheme 6)
to form the indanyl ring system is a 5-endo-trig cyclization
and thus would be expected to be slower than the 6-endo-
trig cyclization that forms the tetrahydronaphthyl system.
We have reported a one step protocol for the conversion
of cyanohydrin ethers to bicyclic â-alkoxy amides through
a sequence of cyanohydrin ether hydrozirconation, acylation,
and intramolecular Friedel-Crafts alkylation. The reactions
generally proceed efficiently and with good to excellent
levels of diastereocontrol. These reactions proceed in a
reasonable time frame at ambient temperature. For substrates
in which cyclization is not kinetically competitive with
Scheme 6. Relative Cyclization Rates as a Function of the
Initial Intermediate
intermediate acylimine decomposition through tautomeriza-
tion, the bicyclic product can be formed by a two step
sequence. In this sequence, the acylimine is trapped through
a rapid reaction with MeOH and acyliminium ion formation
is effected by treating the resulting acyl aminal with
TMSOTf. The ability to vary functional groups on the arene,
the acyl group, and the alkoxy group and the capacity to
form five- and six-membered rings make this route highly
ammenable to applications in diversity oriented synthesis.
Acknowledgment. We thank the National Institutes of
Health (P50-GM067082) and the National Science Founda-
tion (CHE-0139851) for generous financial support of this
work.
Supporting Information Available: Schemes for sub-
strate preparation, experimental procedures for all reactions
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) (a) Sugiura, M.; Kobayashi, S. Org. Lett. 2001, 3, 477. (b) Sugiura,
M.; Hagio, H.; Hirabayashi, R.; Kobayashi, S. J. Am. Chem. Soc. 2001,
123, 12510. For a related procedure, see: Fleming, J. J.; Williams, K.; Du
Bois, J. J. Am. Chem. Soc. 2003, 125, 2028.
(14) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 738.
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