γ-oxygenation of α,β-unsaturated esters by vinylogous O-nitroso mukaiyama aldol reaction

Article abstract of DOI:10.1021/ol1021433

A practical procedure has been developed for γ-oxygenation of α,β-unsaturated esters by a vinylogous O-nitroso Mukaiyama aldol reaction followed by a one-pot N-O bond heterolysis of the in situ generated γ-aminoxy-α,β-unsaturated esters.

Full text of DOI:10.1021/ol1021433

ORGANIC
LETTERS
2010
Vol. 12, No. 21
5072-5074
γ-Oxygenation of r,ꢀ-Unsaturated
Esters by Vinylogous O-Nitroso
Mukaiyama Aldol Reaction
Guo-Qiang Tian, Jiong Yang,* and Kellymar Rosa-Perez
Department of Chemistry, Texas A&M UniVersity, College Station,
Texas 77843-3255, United States
yang@mail.chem.tamu.edu
Received September 8, 2010
ABSTRACT
A practical procedure has been developed for γ-oxygenation of r,ꢀ-unsaturated esters by a vinylogous O-nitroso Mukaiyama aldol reaction
followed by a one-pot N-O bond heterolysis of the in situ generated γ-aminoxy-r,ꢀ-unsaturated esters.
R-Oxygenation of carbonyl compounds is an important
method for C-O bond formation. A number of reactions
have been developed for this purpose. Most of them rely on
oxidation of enolate or enol ether intermediates.1 A recent
variant based on nitroso aldol reactions to give R-aminoxy
carbonyl compounds has also been developed.2 In principle,
a vinylogous extension of the R-oxygenation reactions to
γ-enolizable R,ꢀ-unsaturated carbonyl compounds may be
used to prepare γ-hydroxy-R,ꢀ-unsaturated carbonyl com-
pounds,3 structural motifs that are common to natural
products. Indeed, oxidation of dienol ethers has been reported
for vinylogous oxygenation of R,ꢀ-unsaturated carbonyl
compounds in isolated cases.4 However, as frequently
encountered in vinylogous extensions of carbonyl group
transformations, such oxidation reactions are sometimes
complicated by unpredictable regioselectivities, and both R-
and γ-oxygenation products may be generated. Thus, we
were intrigued by the possibility of applying the vinylogous
Mukaiyama aldol reaction with nitrosobenzene for γ-ami-
noxylation of R,ꢀ-unsaturated carbonyl compounds. Ad-
ditionally, we expected that the N-O bond of the in situ
generated γ-aminoxy moiety would be heterolytically cleaved
by excess nitrosobenzene and lead to a one-pot procedure
to γ-hydroxy-R,ꢀ-unsaturated carbonyl compounds.5
(2) For reviews of O-nitroso aldol reactions, see: (a) Yamamoto, H.;
Kawasaki, M. Bull. Chem. Soc. Jpn. 2007, 80, 595–607. (b) Yamamoto,
H.; Momiyama, N. Chem. Commun. 2005, 3514–3525. (c) Janey, J. M.
Angew. Chem., Int. Ed. 2005, 44, 4292–4300. (d) Plietker, B. Tetrahedron:
Asymmetry 2005, 16, 3453–3459. (e) Merino, P.; Tejero, T. Angew. Chem.,
Int. Ed. 2004, 43, 2995–2997. For some references, see: (f) Momiyama,
N.; Yamamoto, H. Org. Lett. 2002, 4, 3579–3582. (g) Momiyama, N.;
Yamamoto, H. Angew. Chem. Int., Ed. 2002, 41, 2986–2988. (h) Momiyama,
N.; Yamamoto, H. J. Am. Chem. Soc. 2003, 125, 6038–6039; correction
J. Am. Chem. Soc. 2004, 126, 6498. (i) Zhong, G. Angew. Chem., Int. Ed.
2003, 42, 4247–4250. (j) Brown, S. P.; Brochu, M. P.; Sinz, C. J.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808–10809. (k)
Bøgevig, A.; Sundøn, H.; Co´rdova, A. Angew. Chem., Int. Ed. 2004, 43,
1109–1112. (l) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Shoji, M. Angew.
Chem., Int. Ed. 2004, 43, 1112–1115. (m) Momiyama, N.; Torii, H.; Saito,
S.; Yamamoto, H. Proc. Nat. Acad. Sci. U.S.A. 2004, 101, 5374–5378. (n)
Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2005, 127, 1080–1081.
(o) Lu, M.; Zhu, D.; Lu, Y.; Zhen, X.; Tan, B.; Xu, Z.; Zhong, G. J. Am.
Chem. Soc. 2009, 131, 4562–4563. (p) Yanagisawa, A.; Takeshita, S.; Izumi,
Y.; Yoshida, K. J. Am. Chem. Soc. 2010, 132, 5328–5329.
(1) For leading references, see: (a) Rubottom, G. M.; Vazques, M. A.;
Pelegrina, D. R. Tetrahedron Lett. 1974, 4319–4322. (b) Vedejs, E. J. Am.
Chem. Soc. 1974, 96, 5944–5946. (c) Davis, F. A.; Chen, B.-C. Chem. ReV.
1992, 92, 919–934. (d) Morikawa, K.; Park., J.; Andersson, P. G.;
Hashiyama, T.; Sharpless, K. B. J. Am. Chem. Soc. 1993, 115, 8463–8464.
(e) Adam, W.; Fell, R. T.; Stegmann, V. R.; Saha-Moller, C. R. J. Am.
Chem. Soc. 1998, 120, 708–714. (f) Zhu, Y.; Tu, Y.; Yu, H.; Shi, Y.
Tetrahedron Lett. 1998, 39, 7819–7822. (g) Paju, A.; Kanger, T.; Pehk, T.;
Lopp, M. Tetrahedron: Asymmetry 2002, 13, 7321–7326.
(3) (a) Fusion, R. C. Chem. ReV. 1935, 16, 1–27. (b) Krishnamurthy, S.
J. Chem. Educ. 1982, 59, 543–547. (c) Bruneau, P.; Tylor, P. J.; Wilkinson,
A. J. J. Chem. Soc., Perkin Trans. 2 1996, 2263–2269. (d) Denmark, S. E.;
Heemstra, J. R., Jr.; Beutner, G. L. Angew. Chem., Int. Ed. 2005, 44, 4682–
4698. (e) Casiraghi, G.; Zanardi, F. Chem. ReV. 2000, 100, 1929–1972.
10.1021/ol1021433  2010 American Chemical Society
Published on Web 10/11/2010

We put our hypothesis to test using the tert-butyldim-
ethysilyl ketene acetal (1a) of (E)-tert-butyl pent-3-enoate
as a model substrate for reaction with nitrosobenzene under
acidic conditions.6b Our initial experiments with HOAc,
TsOH, or TfOH as the activator in methylene chloride were
not successful, and most of the starting materials appeared
to be hydrolyzed under the reaction conditions (Table 1,
Table 2. Substrate Scope of the γ-Oxygenation Reactiona
Table 1. Conditions for the γ-Oxygenation Reaction
entrya
activator
HOAc
TsOH
TfOH
TMSOTf
HF-Py
HF-Py
solvent
2a (%)
1
2
3
4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
(CH2Cl)2
toluene
CH2Cl2
CH2Cl2
MeOH
nd
nd
nd
nd
67
32
9
<5
5
6b
7
HF-Py
8
KF + HOAc
TBATc + HOAc
HOAc
9
<5
10d
4 (64e)
a All reactions were carried out with 2.4 equiv of nitrosobenzene and
2.4 equiv of HF-Py in CH2Cl2 at -78 °C. While the time needed for
completion of the reactions varies, all the reactions were carried out for
48 h before warming up to 10 °C over 2 h. b The yields may have been
negatively affected by the relatively low boiling point of the products and/
or the low stability of the starting materials. c A mixture of R- and
γ-oxidation products (R:γ ) 1:4). d A mixture of R- and γ-oxidation
products (R:γ ) 1.9:1).
a Unless specified, these reactions were carried out with 2.4 equiv of
nitrosobenzene and 2.4 equiv of the activator in the specified solvent at
-78 °C for 5 h, warmed to 10 °C over 2 h. b The reaction was carried out
at-30°C,warmedto10°C.c TBAT)tetrabutylammoniumdifluorotriphenylsilicate.
d The reaction was carried out with 2.4 equiv of nitrosobenzene and 2.4
equiv of acetic acid at -78 °C, warmed to rt over 2 h. e The yield of 3.
entries 1-3). No desired product was isolated either when
TMSOTf was used (entry 4). Thus we were excited by the
finding that γ-hydroxy-R,ꢀ-unsaturated ester 2a was indeed
formed when the reaction was carried out in methylene
chloride with HF-Py as the activator (entry 5). No R-oxy-
genation product could be detected. Using 1,2-dichloroethane
or toluene as the solvent led to inferior results (entries 6 and
7). Other fluoride sources (entries 8 and 9) were also tested
but proved to be ineffective for the reaction. Unexpectedly,
an (E,E)-γ-nitrone 3 was formed as the only identifiable
product when the reaction was carried out in methanol with
acetic acid as the additive (entry 10).7
addition of the silyl ketene acetals to a dichloromethane
solution of 2.4 equiv of nitrosobenzene and 2.4 equiv of HF-
Py at -78 °C, followed by warming up to 10 °C over 2 h.
Consistent with those observed for vinylogous Mukaiyama
aldol reactions, (E)- double bonds were exclusively formed
in all of the acyclic γ-hydroxy-R,ꢀ-unsaturated ester prod-
ucts. γ-Selective oxidation was generally observed for acyclic
silyl ketene acetals except for entry 10 where a mixture (∼1:
4) of the R- and γ-oxidation products was generated. The
electronic effects of the phenyl group might be responsible
for the impaired regioselectivity. The oxygenation reactions
appear to be most efficient with the silyl ketene acetals of
γ-monosubstituted R,ꢀ-unsaturated esters and not affected
much by the identities of the silyl and alkoxy groups or the
double bond geometry of the silyl ketene acetals (entries 3, 5,
and 6; however, we were unable to explain why the yield of
entry 4 is comparatively low). Since vinylogous Mukaiyama
aldol reactions typically occur through open transition states
with the sp2 carbon at the γ-position directly involved,3 it is at
first surprising that substitutions at the R- and ꢀ- positions
(entries 11-13) affect reaction efficiencies more than those at
the γ- position (entry 14). We surmise that the reduced reaction
efficiencies of the R- and ꢀ-substituted silyl ketene acetals may
be caused more by their reduced stability under the reaction
conditions than by their differential reactivities in the vinylogous
O-nitroso Mukaiyama aldol reactions. A cyclic silyl ketene
acetal (entry 15) of methyl cyclohexene-1-carboxylate was also
We applied the oxidation reaction condition to a panel of
silyl ketene acetals prepared from representative R,ꢀ-
unsaturated esters (Table 2).6 These reactions consisted of
(4) For examples, see: (a) Carret, S.; Depres, J. P. Angew. Chem., Int.
Ed. 2007, 46, 6870–6873. (b) Suryawanshi, S. N.; Fuchs, P. L. J. Org.
Chem. 1986, 51, 902–921. (c) Siegel, C.; Gordon, P. M.; Uliss, D. B.;
Handrick, G. R.; Dalzell, H. C.; Razdan, R. K. J. Org. Chem. 1991, 56,
6865–6872. (d) Blackburn, T. J.; Helliwell, M.; Kilner, M. J.; Lee, A. T.;
Thomas, E. J. Tetrahedron Lett. 2009, 50, 3550–3554.
(5) Ramachary, D. B.; Barbas, C. F., III Org. Lett. 2005, 7, 1577–1580.
(6) (a) Cameron, D. W.; Looney, M. G.; Pattermann, J. A. Tetrahedron
Lett. 1995, 36, 7555–7558. (b) Hassfeld, J.; Christmann, M.; Kalesse, M.
Org. Lett. 2001, 3, 3561–3564. (c) Huang, D. S.; Hartwig, J. F. Angew.
Chem., Int. Ed. 2010, 49, 5757–5761.
(7) The (E)-configuration of nitrone 3 was assigned on the basis of the
characteristic 1H NMR chemical shift of the R-methyl group (δH 2.42 ppm
in CDCl3). See: Bartoli, G.; Marcantoni, E.; Petrini, M. J. Org. Chem. 1990,
55, 4456–4459.
Org. Lett., Vol. 12, No. 21, 2010
5073

oxidized by nitrosobenzene under the reaction condition.
However, a mixture (1.9:1) of R- and γ-oxygenation products
was obtained.
Scheme 2. Proposed Mechanism for Nitrone (3) Formation
The γ-oxygenation reactions proceeded through initial
formation of γ-aminoxy-R,ꢀ-unsaturated ester intermediates.8
Nitrosobenzene is an excellent dienophile and readily
undergoes hetero-Diels-Alder reactions with dienes.9 Thus,
in addition to the vinylogous nitroso Mukaiyama aldol
reaction pathway (Scheme 1, pathway A), a mechanistic
excess nitrosobenzene to give nitrone 3.12 While such a
dichotomy of nitrosobenzene reactivities (O- vs N-electro-
philicities and reduction vs oxidation) has been known for
some time,13 it is interesting to observe that two sets of
similar reaction conditions lead to very different reaction
pathways.
Scheme 1. Proposed Oxygenation Reaction Mechanisms
Our preliminary studies to extend the scope of the reaction
showed that silyl dienol ether 5, readily prepared from (-)-
carvone with the Kharasch reagent and trimethylsilyl chlo-
ride,14 can be γ-oxygenated by the vinylogous O-nitroso
Mukaiyama aldol reaction. Acetic acid proved to be a better
promoter than HF-Py in this case and gave (+)-5R-
hydroxycarvone (6) in 60% yield (Scheme 3). This com-
possibility that involves an initial hetero-Diels-Alder reac-
tion of nitrosobenzene with the electron-rich silyl ketene
acetals, followed by ring opening and isomerization of the
thus formed (Z)-double bond, can also be envisioned for
formation of the γ-aminoxy-R,ꢀ-unsaturated ester intermedi-
ates (Scheme 1, pathway B). However, our experimental
results suggest that such a mechanistic pathway is unlikely
since (E)-double bonds are formed exclusively in reactions
of acyclic silyl ketene acetals. In addition, the diene moiety
of the cyclic silyl ketene acetal of methyl 1-cyclohexene-1-
carboxylate (Table 2, entry 15) is locked into a s-trans
configuration that precludes the substrate from participating
in a hetero-Diels-Alder reaction pathway.10
Scheme 3. γ-Oxygenation of (-)-Carvone
pound was previously synthesized in 9 steps from (-)-
carvone and also isolated in small quantities from natural
sources.15,16
In summary, a practical procedure for γ-oxygenation of
R,ꢀ-unsaturated esters is described. To the best of our
knowledge, this constitutes the first report of the vinylogous
nitroso Mukaiyama aldol reaction. Studies to extend the
scope and identify asymmetric versions of the vinylogous
O-nitroso aldol reaction will be the focus of future research.
Formation of nitrone 3 presumably proceeded by initial
formation of a γ-N-phenylhydroxyamino-R,ꢀ-unsaturated
ester (4) by the vinylgous N-nitroso Mukaiyama aldol
reaction (Scheme 2),11 which was further oxidized by the
Acknowledgment. Financial support was provided by
Texas A&M University and The Welch Foundation (A-
1700). Use of the TAMU/LBMS-Applications Laboratory
and Dr. William Russell of Texas A&M University are
acknowledged.
(8) While the reactions were typically carried out in one pot, the
γ-aminoxy-R,ꢀ-unsaturated ester intermediates could be isolated and
characterized. See Supporting Information for full characterization of the
γ-aminoxy-R,ꢀ-unsaturated ester intermediate (7) of Table 2, entry 14.
(9) For some reviews, see: (a) Yamamoto, Y.; Yamamoto, H. Eur. J.
Org. Chem. 2006, 2031–2043. (b) Vogt, P. F.; Miller, M. J. Tetrahedron
1998, 54, 1317–1348. (c) Streith, J.; Defoin, A. Synthesis 1994, 1107–
1117.
Supporting Information Available: Experimental details
and NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(10) One of the reviewers raised an interesting possibility that the
reaction proceeds by an initial N-nitroso aldol reaction followed by a [2,3]-
sigmatropic rearrangement of the resulting R-N-phenylhydroxyamino-ꢀ,γ-
unsaturated ester to give the γ-aminoxy-R,ꢀ-unsaturated ester intermediate.
While we cannot rule out this possibility, related studies of nitroso aldol
reactions with aldehydes and ketones suggest that O- instead of N-nitroso
aldol products are likely to be preferred under the current reaction conditions
as a result of the difference in basicities of the oxygen and nitrogen atoms.
See ref 2a and Cheong, P. H.-Y.; Houk, K. N. J. Am. Chem. Soc. 2004,
126, 13912–13913.
OL1021433
(12) (a) Knight, G. T.; Loadman, M. J. R. J. Chem. Soc. B 1971, 2107–
2112. (b) Knight, G. T.; Pepper, B. Tetrahedron 1971, 27, 6201–6208.
(13) For some reviews: (a) Adam, W.; Krebs, O. Chem. ReV. 2003, 103,
4131–4146. (b) Zuman, P.; Shah, B. Chem. ReV. 1994, 94, 1621–1641.
(14) (a) Krafft, M. E.; Holton, R. A. J. Am. Chem. Soc. 1984, 106, 7619–
7621. (b) Ceccarelli, S. M.; Piarulli, U.; Gennari, C. Tetrehedron 2001, 57,
8531–8542.
(11) For leading references of N-nitroso aldol reactions, see: (a) Lewis,
J. W.; Myers, P. L.; Ormerod, J. A. J. Chem. Soc., Perkin Trans. 1 1972,
2521–2524. (b) Oppolzer, W.; Tamura, O. Tetrahedron Lett. 1990, 31, 991–
994. (c) Oppolzer, W.; Tamura, O.; Sundarababu, G.; Signer, M. J. Am.
Chem. Soc. 1992, 114, 5900–5902. (d) Momiyama, N.; Yamamoto, H.
J. Am. Chem. Soc. 2004, 126, 5360–5361. (e) Kano, T.; Ueda, M.; Takai,
J.; Maruoka, K. J. Am. Chem. Soc. 2006, 128, 6046–6047. (f) Guo, H.-M.;
Cheng, L.; Cun., F.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Chem. Commun.
2006, 429–431. Also see refs 2a, 2m, 2n, and 2p.
(15) Miyashita, M.; Suzuki, T.; Yoshikoshi, A. J. Org. Chem. 1985,
50, 3377–3380
.
(16) (a) Canova, L. An. Acad. Bras. Cienc. 1972, 44, 273–277. (b)
Ichimura, N.; Matsuura, Y.; Kato, Y. Abstracts of Papers, 25th Terupen,
Seiyu oyobi Koryo ni kansuru Toronkai, Yamaguchi, Oct 1981, p 18
.
5074
Org. Lett., Vol. 12, No. 21, 2010