Diastereoselective, Zinc-Catalyzed Alkynylation of α-Bromo Oxocarbenium Ions

Article abstract of DOI:10.1021/acs.orglett.5b01838

We have developed a bromination/alkynylation sequence that enables efficient transformation of simple cyclic enol ethers to difunctionalized products. The success of this strategy relies on a highly diastereselective, zinc-catalyzed addition of terminal a

Full text of DOI:10.1021/acs.orglett.5b01838

Letter
pubs.acs.org/OrgLett
Diastereoselective, Zinc-Catalyzed Alkynylation of α‑Bromo
Oxocarbenium Ions
Tatsiana Haidzinskaya,†,§ Hilary A. Kerchner,‡,§ Jixin Liu,§ and Mary P. Watson*
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States
S
* Supporting Information
ABSTRACT: We have developed a bromination/alkynylation
sequence that enables efficient transformation of simple cyclic enol
ethers to difunctionalized products. The success of this strategy relies
on a highly diastereselective, zinc-catalyzed addition of terminal
alkynes to α-bromo oxocarbenium ions, formed in situ via ionization
of acetal precursors. Using this method, trans-α-alkynyl-β-halo pyran and furan derivatives can be prepared with high
diastereoselectivity and excellent functional group tolerance.
α-Substituted oxygen heterocycles represent a privileged
scaffold in both natural products and bioactive molecules.1 A
powerful approach to deliver α-carbon substituents to these
oxygen heterocycles is the alkynylation of an acetal substrate.
The alkyne can then be elaborated to a range of α-carbon
substituents. However, known methods for the addition of
alkynes to acetals often require either a strong base or a
functionalized alkyne, thereby limiting functional group
tolerance or convenience (Scheme 1A).2,3 Previously, we
nation (Scheme 1A). We now report a zinc-catalyzed
alkynylation of α-halo tetrahydropyranyl and tetrahydrofuranyl
acetals to deliver trans-3-halo-2-alkynyl oxygen heterocycles in
high yields and excellent levels of diasteroselectivity (Scheme
1B). When combined with the efficient preparation of the 3-
halo-2-acetoxy substrates via halogenation of cyclic enol ethers,5
this method enables a difunctionalization of cyclic enol ethers.
The halide substituent not only promotes higher yields in the
alkynylation but also provides the trans-3-bromo-2-alkyl oxygen
heterocycle motif present in a number of marine natural
products,1a−c,6 as well as a handle for further elaboration.2a
We began our investigation with the addition of phenyl
acetylene to 2-acetoxytetrahydropyran, which can be easily
prepared from dihydropyran.7 Although CuI and ZnBr2 were
both effective catalysts in the alkynylation of benzopyranyl
acetals 2 and 3,4b the use of a copper(I) catalyst in the
alkynylation of acetal 8 provided only trace product (20 mol %
Scheme 1. Alkynylations of Acetals
1
CuI, BF3·OEt2, NEt3, Et2O, rt, 24 h, 4% yield by H NMR
analysis). However, desired product 9 was observed when
ZnBr2 was used as catalyst (Table 1, entry 1). The yield of 9
was increased to 50% by using dioxane as solvent (entries 2 and
3), but further attempts to optimize the reaction failed. We
assume that competitive E1 elimination of the oxocarbenium
ion and subsequent polymerization of the resulting dihydropyr-
an prevents higher yields.8
We envisioned that the use of an α-bromo substituent might
electronically disfavor E1 elimination, as well as control
diastereoselectivity and provide a second functional group
handle in the product. trans-3-Bromo-2-acetoxy pyran 4a was
readily prepared in 85% yield and 7:1 dr via bromination of
dihydropyran in acetic acid.5 Alkynylation of acetal 4a resulted
in only 38% yield when dioxane was used as solvent (entry 4).
Use of CH2Cl2 as solvent resulted in an increased yield of 75%
(entry 5). By increasing the equivalents of BF3·OEt2, an 85%
yield of 10 was observed. Under all conditions, a single
reported the addition of unfunctionalized terminal alkynes to
cyclic oxocarbenium ions using either a zinc or copper catalyst.4
We envisioned that this approach may offer a general,
functional-group-tolerant and convenient strategy for the
addition of alkynes to acetals. However, to date, this method
has been limited to oxocarbenium ions that lack β-hydrogens
and therefore cannot undergo decomposition via E1 elimi-
Received: June 25, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01838
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Addition of trimethylsilylacetylene was also effective, allowing
access to terminal alkynes via deprotection of the TMS group
(see below). In every case in Scheme 2, a single diastereomer of
product was observed, consistent with our hypothesis that the
α-bromide may stabilize the oxocarbenium ion via a
bromonium-like structure (see 5 in Scheme 1B). The trans
configuration of product 16 was confirmed by X-ray
crystallography.9 The configurations of other products were
assigned by analogy.
Table 1. Reaction Optimization
b
entry
acetal
solvent
equiv BF3·OEt2
yield (%)
1
2
3
4
5
6
8
Et2O
1.3
1.3
1.3
2.0
2.0
3.0
19
50
28
38
75
85
8
dioxane
CH2Cl2
dioxane
CH2Cl2
CH2Cl2
This halogenation/alkynylation sequence was also successful
in the preparation of other trans-3-halo-2-alkynyl cyclic ethers
(Table 2). As for dihydropyran 11a, this sequence resulted in a
8
4a
4a
4a
a
Table 2. Scope of Halogens and Enol Ethers
Conditions: acetal (0.10 mmol, 1.0 equiv), ZnBr2 (0.010 mmol, 10
mol %), alkyne (0.13 mmol, 1.3 equiv), BF3·OEt2 (0.15 mmol, 1.5
equiv), i-Pr2NEt (0.15 mmol, 1.5 equiv), solvent (0.20 M).
b
1
Determined by H NMR analysis using 1,3,5-trimethoxybenzene as
internal standard.
diastereomer of 10 was formed. A promising, albeit not
synthetically useful, yield was observed when the bromination/
alkynylation was performed in one pot; a 15% yield of alkyne
10 was obtained when dihydropryran 11a was treated with
NBS, followed by ZnBr2, phenyl acetylene, i-Pr2NEt, and BF3·
OEt2.
Under the optimized conditions, a wide variety of terminal
alkynes undergo reaction with α-bromoacetal 4a (Scheme 2).
Scheme 2. Scope of Alkynes
a
Conditions: 11 (1.0 equiv), NBS (1.3 equiv), AcOH (10.0 equiv), 0
b
°C to rt. Yields of single experiments. Acetal 4 (0.50 mmol, 1.0
equiv), ZnBr2 (0.050 mmol, 10 mol %), phenyl acetylene (0.65 mmol,
1.3 equiv), BF3·OEt2 (1.5 mmol, 3.0 equiv), i-Pr2NEt (0.75 mmol, 1.5
equiv), CH2Cl2 (0.18 M), rt, 24 h. Average isolated yields of duplicate
c
d
experiments ( 4%). 17:1 dr. Bromination conditions: 11 (1.0
equiv), NBS (1.3 equiv), AcOH (10.0 equiv), CH2Cl2 (3.0 mL), 0 °C.
e
f
g
NBS was replaced by NCS. 2.9:1 dr. 17:1 dr.
a
Conditions: 11a (11.5 mmol, 1.0 equiv), NBS (1.3 equiv), AcOH
b
single diastereomer for each 3-bromo-2-alkynyl heterocycle
shown in Table 2 (entries 1−4). The bromination and
alkynylation of dihydrofuran 11b proceeded in 71% (17:1 dr)
and 75% yields, respectively, demonstrating that this strategy is
not limited to pyrans (entry 1). Importantly, the bromination
of substituted dihydrofuran 11c proceeded in high diaster-
eoselectivity, ultimately giving a single diastereomer of 3-
bromo-2-alkynyl furan 22c (entry 2). The relative configuration
of 22c was assigned by analogy to the configuration of its acetal
precursor (4c), which was determined by X-ray crystallog-
raphy.9 Isochromene 11d and vinylogous enol ether 11e also
underwent the bromination/alkynylation in high yields (entries
3 and 4). For these latter substrates (11c−11e), the
(10.0 equiv), 0 °C to rt. Acetal 4a (0.50 mmol, 1.0 equiv), ZnBr2
(0.050 mmol, 10 mol %), alkyne (0.65 mmol, 1.3 equiv), BF3·OEt2
(1.5 mmol, 3.0 equiv), i-Pr2NEt (0.75 mmol, 1.5 equiv), CH2Cl2 (0.18
M), rt, 24 h. Average isolated yields of duplicate experiments ( 6%),
c
unless otherwise noted. Result of a single experiment.
With aryl-substituted alkynes, substituents are well tolerated at
the ortho, meta, and para positions. Alkynes with both electron-
rich (12) and electron-poor (13−18) aryl groups can be
utilized. In addition, a range of functional groups are tolerated,
including chloride (13), ether (14), trifluoromethyl (15), nitrile
(16), fluoride (17), and ester (18). Alkynes with aliphatic
substitution are also successful in this alkynylation (19 and 20).
B
DOI: 10.1021/acs.orglett.5b01838
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
bromination reactions were performed in AcOH/CH2Cl2
instead of neat AcOH to avoid decomposition of the bromo
acetal intermediates.
In addition to bromination, chlorination of dihydropyran 11a
can be performed, albeit in lower yield and diastereoselectivity
than the analogous bromination (Table 2, entry 5). Subsequent
alkynylation of the α-chloro acetal delivered 22f in moderate
yield, but excellent diastereoselectivity (17:1 dr). The
analogous iodination was not successful.
ACKNOWLEDGMENTS
■
Acknowledgement is gratefully made to the National Science
Foundation (CAREER CHE 1151364) for support of this
research. H.A.K. thanks the American Chemical Society
Division of Organic Chemistry and GlaxoSmithKline for
summer undergraduate research fellowships. NMR and other
data were acquired at UD on instruments obtained with the
assistance of NSF and NIH funding (NSF CHE 0421224, CHE
1229234, and CHE 0840401; NIH P20 GM103541 and S10
RR02682).
Elaboration of the alkyne products can be accomplished in
high yields to give single diastereomers of products (Scheme
3). For example, hydrogenation of alkyne 10 resulted in
REFERENCES
■
(1) (a) Kennedy, D. J.; Selby, I. A.; Cowe, H. J.; Cox, P. J.; Thomson,
R. H. J. Chem. Soc., Chem. Commun. 1984, 153. (b) Irie, T.; Suzuki, M.;
Masamune, T. Tetrahedron Lett. 1965, 6, 1091. (c) Irie, T.; Suzuki, M.;
Masamune, T. Tetrahedron 1968, 24, 4193. (d) Cai, X.; Chorghade, M.
S.; Fura, A.; Grewal, G. S.; Jauregui, K. A.; Lounsbury, H. A.; Scannell,
R. T.; Yeh, C. G.; Young, M. A.; Yu, S.; Guo, L.; Moriarty, R. M.;
Penmasta, R.; Rao, M. S.; Singhal, R. K.; Song, Z.; Staszewski, J. P.;
Tuladhar, S. M.; Yang, S. Org. Process Res. Dev. 1999, 3, 73. (e) Suzuki,
T.; Koizumi, K.; Suzuki, M.; Kurosawa, E. Chem. Lett. 1983, 1643.
(f) Kool, E. Acc. Chem. Res. 2002, 35, 936. (g) Hocek, M.; Stambasky,
J.; Kocovsky, P. Chem. Rev. 2009, 109, 6729.
Scheme 3. Elaboration of Products
(2) (a) Karadogan, B.; Edwards, N.; Parsons, P. J. Tetrahedron Lett.
1999, 40, 5931. (b) Lubin-Germain, N.; Baltaze, J.-P.; Coste, A.;
Hallonet, A.; Laureano, H.; Legrave, G.; Uziel, J.; Auge, J. Org. Lett.
2008, 10, 725. (c) Zeng, J.; Vedachalam, S.; Xiang, S.; Liu, X.-W. Org.
Lett. 2011, 13, 42.
(3) For addition of alkynes to glycals via allylic substitution, see:
(a) Kusunuru, A. K.; Tatina, M.; Yousuf, S. K.; Mukherjee, D. Chem.
Commun. 2013, 49, 10154. (b) Tatina, M. B.; Kusunuru, A. K.; Yousuf,
S. K.; Mukherjee, D. Org. Biomol. Chem. 2014, 12, 7900.
quantitative formation of tetrahydropyran 23. After depro-
tection of the trimethylsilyl group of alkyne 21, a copper-
catalyzed Click reaction delivers triazole in 71% yield.10 The
bromide also provides a handle for functionalization;
elimination delivers enyne 24 in moderate yield.
In summary, we have developed mild reaction conditions for
the addition of unfunctionalized, terminal alkynes to α-halo
oxocarbenium ions, formed in situ from acetal precursors.
When coupled with halogenation, this method enables the
preparation of difunctionalized oxygen heterocycles from
simple enol ether precursors in excellent diastereoselectivities.
Ongoing efforts are directed toward the application of this
method to additional enol ether substrates, as well as glycals, to
enable efficient preparation of multisubstituted oxygen hetero-
cycles.
(4) (a) Maity, P.; Srinivas, H. D.; Watson, M. P. J. Am. Chem. Soc.
2011, 133, 17142. (b) Srinivas, H. D.; Maity, P.; Yap, G. P. A.; Watson,
M. P. J. Org. Chem. 2015, 80, 4003.
(5) (a) Shelton, J. R.; Cialdella, C. J. Org. Chem. 1958, 23, 1128.
(b) Bateman, G.; Brown, B. R.; Campbell, J. B.; Cotton, C. A.;
Johnson, P.; Mulqueen, P.; O’Neill, D.; Shaw, M. R.; Smith, R. A.;
Troke, J. A. J. Chem. Soc., Perkin Trans. 1 1983, 2903.
(6) For syntheses of these classes of natural products, see: (a) Park,
J.; Kim, B.; Kim, H.; Kim, S.; Kim, D. Angew. Chem., Int. Ed. 2007, 46,
4726. (b) Masamune, T.; Matsue, H.; Murase, H. Bull. Chem. Soc. Jpn.
1979, 52, 127. (c) Burton, J. W.; Clark, J. S.; Derrer, S.; Stork, T. C.;
Bendall, J. G.; Holmes, A. B. J. Am. Chem. Soc. 1997, 119, 7483.
ASSOCIATED CONTENT
* Supporting Information
■
(d) Kruger, J.; Hoffmann, R. W. J. Am. Chem. Soc. 1997, 119, 7499.
̈
S
(e) Crimmins, M. T.; Emmitte, K. A. Org. Lett. 1999, 1, 2029. (f) Baek,
S.; Jo, H.; Kim, H.; Kim, H.; Kim, S.; Kim, D. Org. Lett. 2005, 7, 75.
(7) Iwanami, K.; Aoyagi, M.; Oriyama, T. Tetrahedron Lett. 2006, 47,
4741.
Experimental procedures, X-ray crystal structure, character-
ization data, and spectra of new compounds. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.orglett.5b01838.
(8) Kamio, V. K.; Meyersen, K.; Schulz, R. C.; Kern, W. Makromol.
Chem. 1966, 90, 187.
(9) CCDC 973169 (16) and 1404542 (4c) contain the
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic Data
Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
(10) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mpwatson@udel.edu.
Present Addresses
†The Chemours Company FC, LLC, Experimental Station
402/4331, 200 Powder Mill Rd., Wilmington, DE 19803,
Tatsiana.Haidzinskaya@chemours.com.
‡University of Michigan, Department of Chemistry, 930 N.
University Ave., Ann Arbor, MI 48109, hkerch@umich.edu.
Author Contributions
§T.H., H.A.K., and J.L. contributed equally.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.5b01838
Org. Lett. XXXX, XXX, XXX−XXX