Catalytic carbon insertion into the β-vinyl C-H bond of cyclic enones with alkyl diazoacetates

Article abstract of DOI:10.1021/ol4000026

The first example of the boron Lewis acid catalyzed C_sp2-H functionalization of cyclic enones was achieved using diazoacetates. The insertion of the carbon atom of diazoacetates utilizes BF₃? Et₂O or a newly designed oxaza

Full text of DOI:10.1021/ol4000026

ORGANIC
LETTERS
2013
Vol. 15, No. 7
1428–1431
Catalytic Carbon Insertion into the β‑Vinyl
CÀH Bond of Cyclic Enones with Alkyl
Diazoacetates
Sung Il Lee,†,‡ Byung Chul Kang,† Geum-Sook Hwang,*,‡ and Do Hyun Ryu*,†
Department of Chemistry, Sungkyunkwan University, Suwon, 440-746, Korea, and
Korea Basic Science Institute, Seoul, 136-713, Korea
dhryu@skku.edu; gshwang@kbsi.re.kr
Received January 1, 2013
ABSTRACT
The first example of the boron Lewis acid catalyzed Csp2ÀH functionalization of cyclic enones was achieved using diazoacetates. The insertion of
the carbon atom of diazoacetates utilizes BF3•Et2O or a newly designed oxazaborolidinium ion as a catalyst to afford β-functionalized cyclic enones
from simple cyclic enones in a single step and high yields. The reaction mechanism was investigated with deuterium labeled 2-cyclohexen-1-one.
The selective functionalization of the CÀH bond is one
of the most progressive and challenging topics in current
organic chemistry.1 An intermolecular CÀH functionali-
zation method offers a more ideal strategy for the forma-
tion of complex molecules. Recently, our group reported
an oxazaborolidinium ion catalyzed asymmetric cyclopro-
panation of substituted acrolein with diazoacetate.2 During
the course of our study, a trace amount of CÀH inserted
acrolein was isolated (Scheme 1). The Noels3 and Maruoka4
groups have reported similar CÀH inserted methacrolein
side products in cyclization reactions. We were interested in
the potential of this reaction and investigated suitable
reaction conditions for selective CÀH functionalization.
† Sungkyunkwan University.
‡ Korea Basic Science Institute.
Scheme 1. Oxazaborolidinium Ion Catalyzed
Cyclopropanation and the CÀH Functionalization Reaction
(1) For examples of CÀH functionalization reactions, see the follow-
ing. Formyl Csp2ÀH: (a) Gutsche, C. D. Org. React. 1954, 8, 364. (b)
Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258. (c)
Wommack, A. J.; Moebius, D. C.; Travis, A. L.; Kingsbury, J. S. Org.
Lett. 2009, 11, 3202. (d) Li, W.; Wang, J.; Hu, X.; Shen, K.; Wang, W.;
Chu, Y.; Lin, L.; Liu, X.; Feng, X. J. Am. Chem. Soc. 2010, 132, 8532. (e)
Gao, L.; Kang, B. C.; Hwang, G.-S.; Ryu, D. H. Angew. Chem., Int. Ed.
2012, 51, 8322. Allylic Csp3ÀH: (f) Davies, H. M. L.; Ren, P. J. Am.
Chem. Soc. 2001, 123, 2070. (g) Bykowski, D.; Wu, K.-H.; Doyle, M. P.
J. Am. Chem. Soc. 2006, 128, 16038. (h) Ventura, D. L.; Li, Z.; Coleman,
M. G.; Davies, H. M. L. Tetrahedron 2009, 65, 3052. (i) Gutekunst,
W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976. (j) Wang, J.;
Boyarskikh, V.; Rainier, J. D. Org. Lett. 2011, 13, 700. (k) Wang,
J.-C.; Xu, Z.-J.; Guo, Z.; Deng, Q.-H.; Zhou, C.-Y.; Wan, X.-L.; Che,
C.-M. Chem. Commun. 2012, 48, 4299. Aromatic Csp2ÀH: (l) Haldar, P.;
Kar, G. K.; Ray, J. K. Tetrahedron Lett. 2003, 44, 7433. (m) Rodriguez-
β-Substituted enones are versatile intermediates in the
synthesis of biologically active molecules and pharma-
ceuticals. Reported methods to prepare β-substituted en-
ones are illustrated in Scheme 2. One method is initiated
by Michael addition and R-selenylation of an enone.
ꢀ
Cardenas, E.; Sabala, R.; Romero-Ortega, M.; Ortiz, A.; Olivo, H. F.
Org. Lett. 2012, 14, 238. (n) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu,
J.-Q. Acc. Chem. Res. 2012, 45, 788. (o) Ye, T.; McKervey, A. Chem.
Rev. 1994, 94, 1091. Csp3ÀH: (p) Davies, H. M. L. Angew. Chem., Int.
Ed. 2006, 45, 6422. (q) Slattery, C. N.; Ford, A.; Maguire, A. R.
Tetrahedron 2010, 66, 6681. (r) Doyle, M. P.; Ratnikov, M.; Liu, Y.
Org. Biomol. Chem. 2011, 9, 4007.
ꢀ
(3) (a) Noels, A. F.; Braham, J. N.; Hubert, A. J.; Teyssie, P. J. Org.
Chem. 1977, 42, 1527. (b) Noels, A. F.; Braham, J. N.; Hubert, A. J.;
ꢀ
Teyssie, P. Tetrahedron 1978, 34, 3495.
(2) Gao, L.; Hwang, G.-S.; Ryu, D. H. J. Am. Chem. Soc. 2011, 133,
20708.
(4) Kano, T.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2006,
128, 2174.
r
10.1021/ol4000026
Published on Web 03/08/2013
2013 American Chemical Society

Subsequent oxidation of selenium and pyrolytic syn elim-
ination afforded the desired β-substituted enone (eq 1).5
Other methods for the preparation of β-functionalized
enones involve β-halo or alkoxy substituted enones
(eq 2).6 Recently, a novel one-pot sequential prepara-
tive method was independently developed by Matsuo7
and Kerr8 et al. (eq 3).
insertion product.10 Our next exploration was carried out
with tert-butyl benzyldiazoacetate and 2-cyclohexen-1-one
in the presence of various Lewis acids. The central chal-
lenge was to identify a catalytic system that would avoid
decomposition of the diazoacetate. Brønsted acids (Table 1,
entry 1) and metal Lewis acids such as TiCl4, Sc(OTf)3, and
SnCl4 (Table 1, entries 2À4) did not act as catalysts and
rapidly decomposed the diazoacetate. Only BF3•Et2O ex-
hibited catalytic activity toward CÀH insertion (Table 1,
entry 5). When the reaction was carried out at 0 °C in dichlo-
romethane, 20 mol % of BF3•Et2O afforded the desired
insertion product in 37% yield. To improve the yield,
2-cyclohexen-1-one was used as the limiting reactant. The
reaction was successfully performed with 2 equiv of diazoa-
cetate to furnish the β-substituted cyclohexenone in 85%
yield (Table 1, entry 6).
Scheme 2. Reported Methods for β-Substituted Cyclohexenone
Table 1. Lewis Acid Catalyzed Carbon Insertion Reactions with
2-Cyclohexen-1-one and Alkyl Benzyldiazoacetate
Scheme 3. Boron Lewis Acid Catalyzed Carbon Insertion Re-
action of Cyclic Enones
entry
R
Lewis acid
x
temp (°C)
yield(%)a
1b
2b
3b
4b
5b
6c
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Me
TfOH
20
20
20
20
20
20
20
20
20
10
0
10
10
20
20
37
85
52
50
52
88
TiCl4
0
Sc(OTf)3
SnCl4
0
0
We were inspired by a selective insertion of the carbon
atom of diazoacetates into the β-vinyl CÀH bond to afford
a β-substituted enone in a single step from a nonfunctio-
nalized, commercially available enone. In this report, we
describe the boron Lewis acid catalyzed Csp2ÀH functio-
nalization of cyclic enones using diazoacetates.9 We also
document our mechanistic findings with kinetic isotope
effect data from β-deuterated 2-cyclohexen-1-one (Scheme 3).
Investigation of the CÀH functionalization was initiated
with the screening of suitable enone structures. Interestingly,
cyclic R,β-unsaturated ketones predominantly afforded the
desired product, whereas acyclic enones did not yield the
BF3•Et2O
BF3•Et2O
BF3•Et2O
BF3•Et2O
BF3•Et2O
BF3•Et2O
0
0
7c
À20
0
8c
9c
Bn
0
10c
t-Bu
0
a Isolated yield. b The reaction was performed using 1.2 equiv of
2-cyclohexen-1-one and 1.0 equiv of tert-butyl benzyldiazoester. c The
reaction was performed using 1.0 equiv of 2-cyclohexen-1-one and
2.0 equiv of alkyl benzyldiazoester.
At À20 °C, the reaction stopped before reaching com-
pletion (Table 1, entry 7). The ethyl or benzyl ester sub-
stituted diazoester did not completely generate the inser-
tion product (Table 1, entries 8 and 9). Fortunately, use of
10 mol % of the catalyst successfully catalyzed the reaction
and furnished the CÀH inserted cyclohexenone in 88%
yield (Table 1, entry 10).
(5) (a) Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am. Chem. Soc. 1975,
97, 5434. (b) Liotta, D.; Saidane, M.; Barnum, C.; Zima, G. Tetrahedron
1985, 41, 4881. (c) Kim, J. H.; Lim, H. J.; Cheon, S. H. Tetrahedron 2003,
59, 7501. (d) Takemoto, T.; Fukaya, C.; Yokoyama, K. Tetrahedron
Lett. 1989, 30, 723.
(6) (a) Lee, K.; Kim, H.; Mo, J.; Lee, P. H. Chem.;Asian J. 2011, 6,
2147. (b) d’Augustin, M.; Palais, L.; Alexakis, A. Angew. Chem., Int. Ed.
ꢀ
2005, 44, 1376. (c) Henon, H.; Mauduit, M.; Alexakis, A. Angew. Chem.,
After optimization of the CÀH functionalization reaction,
the scope of this methodology was investigated with various
diazoacetates and cyclic enones (Scheme 4, Method A). For
benzyl or allyl substituted diazoacetates, six- and five-
membered cyclic enones provided the insertion products
in high yield (Scheme 4, 3aÀ3c, 3l, 3m). For tert-butyl
ethyldiazoacetate, the yield decreased to 71% under the
optimized reaction conditions. Fortunately, the reac-
tion carried out at À20 °C furnished the corresponding
β-substituted, cyclic enone in excellent yield regardless
of ring size (Scheme 4, 3d, 3n). Methyl and isopropyl
Int. Ed. 2008, 47, 9122. (d) Shintani, R.; Takeda, M.; Nishimura, T.;
Hayashi, T. Angew. Chem., Int. Ed. 2010, 49, 3969.
(7) Matsuo, J.; Aizawa, Y. Chem. Commun. 2005, 2399.
(8) Kerr, W. J.; Pearson, C. M.; Thurston, G. J. Org. Biomol. Chem.
2006, 4, 47.
(9) For selected examples of Lewis acid catalyzed functionalization
of ketones with diazoacetates, see: (a) Hashimoto, T.; Naganawa, Y.;
Maruoka, K. J. Am. Chem. Soc. 2009, 131, 6614. (b) Li, W.; Liu, X.;
Hao, X.; Hu, X.; Chu, Y.; Cao, W.; Qin, S.; Hu, C.; Lin, L.; Feng, X. J.
Am. Chem. Soc. 2011, 133, 15268. (c) Li, W.; Liu, X.; Hao, X.; Cai, Y.;
Lin, L.; Feng, X. Angew. Chem., Int. Ed. 2012, 51, 8644.
(10) Acyclic enone produced 2-pyrazoline as a major product. See:
Novikov, R. A.; Platonov, D. N.; Dokichev, V. A.; Tomilov, Y. V.;
Nefedov, O. M. Russ. Chem. Bull., Int. Ed. 2010, 59, 985.
Org. Lett., Vol. 15, No. 7, 2013
1429

Scheme 4. Scope of the CÀH Functionalization (all yields refer to pure isolated product)
a The reaction was performed using 1.0 equiv of cyclic enone and 2.0 equiv of tert-butyl diazoester. b The reaction was performed using 1.0 equiv of
cyclic enone and 1.2 equiv of tert-butyl diazoester. c Reaction time is 5 h. d Reaction time is 3 h. e 50 mol % BF3•Et2O used. f 100 mol % BF3•Et2O used.
g Reaction time is 16 h. h 50 mol % of oxazaborolidinium catalyst used.
substituted diazoacetates required a high catalyst load-
ing and gave the insertion product in moderate yield
(Scheme 4, 3e and 3f, 3o, respectively). We suspect that
Scheme 5. Preparation of Oxazaborolidinium Ion
the high steric congestion of isopropyldiazoacetate re-
duces its reactivity with the cyclic enone.
To further evaluate the broad feasibility of the CÀH
functionalization reaction, we focused on developing a
more suitable boron Lewis acid catalyst. The oxazabo-
rolidinium ion is a powerful Lewis acid that catalyzes a wide
range of organic reactions.11 We anticipated that the bulki-
ness of the oxazaborolidinium ion would inhibit the re-
activity of boron toward the diazoester and selectively
activate the cyclic enone. We designed the novel and easily
accessible achiral oxazaborolidinium ion catalyst 6. Com-
mercially available 2-(methylamino)ethanol (4) and 1-naph-
thylboroxine (5) were selected for the oxazaborolidine as
a precursor of 6. Oxazaborolidinium ion catalyst 6 was
prepared by activation of the precursor with triflic imide
(Scheme 5). The CÀH functionalization reaction with
tert-butyl benzyldiazoacetate and 2-cyclohexen-1-one in
the presence of 20 mol % of catalyst 6 furnished 3a in
quantitative yield without decomposition of the diazo-
ester (Scheme 4, method B).
In most of the six-membered cyclic enone cases, oxaza-
borolidinium ion 6 afforded improved yields of CÀH
insertion products compared to BF3•Et2O and showed a
wide substrate scope (Scheme 4, 3aÀ3d, 3fÀ3k).12 The
insertion reaction with 6-methyl-2-cyclohexen-1-one was
carried out with both catalysts. While BF3•Et2O afforded
3h and 3i in moderate yields, the same reaction with cata-
lyst 6 furnished the corresponding CÀH inserted product
in excellent yield.13 Oxazaborolidinium ion 6 effectively
catalyzed the reaction with 5-disubstituted cyclohexen-
ones to quantitatively produce the β-functionalized enone
(Scheme 4, 3j, 3k). For five-membered cyclic enones,
BF3•Et2O was a more suitable catalyst than oxazaboroli-
dinium ion 6 (Scheme 4, 3lÀ3o). In contrast, the BF3•Et2O
catalyzed insertion reaction with 2-cyclohepten-1-one was
(11) (a) Senapati, B. K.; Hwang, G.-S.; Lee, S.; Ryu, D. H. Angew.
Chem., Int. Ed. 2009, 48, 4398. (b) Gao, L.; Hwang, G.-S.; Lee, M. Y.;
Ryu, D. H. Chem. Commun. 2009, 5460. (c) Senapati, B. K.; Gao, L.;
Lee, S. I.; Hwang, G.-S.; Ryu, D. H. Org. Lett. 2010, 12, 5088. (d) Corey,
E. J. Angew. Chem., Int. Ed. 2009, 48, 2100. (e) Ryu, D. H.; Corey, E. J.
J. Am. Chem. Soc. 2005, 127, 5384.
(12) Methyl tert-butyldiazoacetate was rapidly decomposed in the
presence of oxazaborolidinium catalyst 6.
(13) A mixture of diastereomers (∼1:2) was formed.
1430
Org. Lett., Vol. 15, No. 7, 2013

unfruitful (Scheme 4, 3q, 3r; Method A), with decomposi-
tion of the diazoester occurring faster than formation of
the product. On the other hand, catalyst 6 was compatible
with the diazoester under À20 °C and afforded the cyclo-
heptenone CÀH insertion product in moderate yield
(Scheme 4, 3q, 3r).14
Scheme 7. Kinetic Isotope Effect Experiment
Scheme 6. Evidence for Intramolecular CÀH Migration
Pathway
Scheme 8. Proposed Mechanism for the CÀH Functionalization
Reaction
Our attention next turned to elucidating the mechanism
of this novel transformation. On treatment of tert-butyl
benzyldiazoacetate with 3-deuterio-2-cyclohexen-1-one (7)
under the optimized conditions, the insertion reaction pro-
ceeded to give the corresponding deuterated product 8
(Scheme 6, eq 1). The NMR spectrum revealed >98% de-
uterium incorporated at the R-position of the tert-butyl
ester. In addition, a double-labeling competitive experi-
ment proved that the insertion reaction proceeded in an
intramolecular hydride transfer manner (Scheme 6, eq 2).
For further mechanistic insight, a kinetic isotope effect
(KIE) experiment was conducted with a mixture of deut-
erated and nondeuterated cyclohexenone, and the kH/kD
was found to be 0.77 (Scheme 7). These experiments sug-
gest that the insertion is under the influence of an inverse
secondary kinetic isotope effect (inverse SKIE).15
On the basis of the above observations, a mechanistic
proposal is presented in Scheme 8. There are two plausible
pathways for CÀH functionalization: one path consists of
a 1,4-additionand subsequentβ-hydridemigrationprocess
(path a),16 and the second possible pathway involves initial
formation of a 1-pyrazoline (11) by 1,3-dipolar cycloaddi-
tion and subsequent CÀN cleavage to provide the same
intermediate 10 (path bfc).17 According to the KIE
experiment, a hybridization change of the 3-C from sp2
to sp3 by 1,4-addition is the rate-determining step. Inter-
estingly, 1-pyrazoline 11 resulting from 1,3-dipolar cy-
cloaddition was observed when R is ethyl (path b), and a
slow transformation of the 1-pyrazoline to the insertion
product could be monitored by TLC (path c). Since the
1-pyrazoline rapidly tautomerizes under protic conditions,
2-pyrazoline 12 could be isolated after quenching with
water.
In conclusion, we have developed a boron Lewis acid
catalyzed Csp2ÀH functionalization reaction of cyclic en-
ones using diazoacetates. The insertion of the carbon atom
of diazoacetates utilizes BF3•Et2O or a newly designed
oxazaborolidinium ion as a catalyst to afford β-functiona-
lized cyclic enones from simple cyclicenones ina single step
and high yields. We believe that the resulting β-functiona-
lized enones could be highly valuable for the synthesis of
useful complex molecules. Further extension of this re-
searchtothecatalytic asymmetricversion of thisreaction is
now in progress.
Acknowledgment. This work has supported by grants
NRF-2012-R1A6A1040282 (Priority Research Centers
Program) and NRF-2011-0029186 (Midcareer Researcher
Program) and the Korea Basic Science Institute (T33409).
(14) The yields based on recovered starting material for 3g, 3l, 3n, and
3pÀ3r are 99% (Method B).
Supporting Information Available. Experimental de-
tails and chracterization data for products. This material
is available free of charge via the Internet at http://pubs.
acs.org.
(15) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic
Chemistry; University Science: 2005; pp 428À430.
(16) Snider, B. B.; Rodini, D. J.; van Straten, J. J. Am. Chem. Soc.
1980, 102, 5872.
(17) Hashimoto, T.; Naganawa, Y.; Kano, T.; Maruoka, K. Chem.
Commun. 2007, 5143; see Supporting Information.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 7, 2013
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