Mechanism of the regio- and diastereoselective ring expansion reaction using trimethylsilyldiazomethane

Article abstract of DOI:10.1021/ol302032w

An equatorial attack of TMS-diazomethane was determined to be the first step of the BF₃-promoted ring expansion reaction of six-membered ketones using TMS-diazomethane. The migration reaction occurred in a conformation in which the carbonyl oxygen and the TMS group were antiperiplanar to predominantly afford trans-seven-membered ketones.

Full text of DOI:10.1021/ol302032w

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4564–4567
Mechanism of the Regio- and
Diastereoselective Ring
Expansion Reaction Using
Trimethylsilyldiazomethane
Takeo Sakai, Satoshi Ito, Hiroki Furuta, Yuki Kawahara, and Yuji Mori*
Faculty of Pharmacy, Meijo University, Tempaku-ku, Nagoya, 468-8503, Japan
mori@meijo-u.ac.jp
Received July 23, 2012
ABSTRACT
An equatorial attack of TMS-diazomethane was determined to be the first step of the BF3-promoted ring expansion reaction of six-membered
ketones using TMS-diazomethane. The migration reaction occurred in a conformation in which the carbonyl oxygen and the TMS group were
antiperiplanar to predominantly afford trans-seven-membered ketones.
TMS-diazomethane is one of the most common reagents
for homologation reactions used to construct medium-
sized rings.1,2 The ring expansion reaction using TMS-
diazomethane is usually regioselective because a less
substituted carbon migrates more readily than a more sub-
stituted carbon. Double-expansion reactions to produce
larger-sized rings are suppressed because the initial pro-
ducts are less-reactive silylketones. These features make
this reaction attractive and feasible in many situations3
with the aid of Lewis acids such as BF3,4 trialkyl aluminums,5
and scandium salts.6,7
In our synthetic studies of natural polycyclic ethers, we
often use the ring expansion reaction with TMS-diazo-
methane for the construction of seven-membered ether
rings.7b,8 As shown in Scheme 1, the major product is
(1) For a recent review of TMS-diazomethane, see: Shioiri, T.;
Aoyama, T. Trimethylsilyldiazomethane. (First updated by Snowden,
T.) In Reagents for Silicon-Mediated Organic Synthesis; Fuchs, P. L., Ed.;
Handbook of Reagents for Organic Synthesis; John Wiley & Sons Ltd.:
United Kingdom, 2011; pp 590ꢀ598.
Scheme 1. Ring Expansion Reaction of a Tetrahydropyran-3-
one with TMS-Diazomethane
(2) For a review of the ring expansion reaction to seven-membered rings,
see: Kantorowski, E. J.; Kurth, M. J. Tetrahedron 2000, 56, 4317–4353.
(3) For recent applications of the ring expansion reaction using TMS-
diazomethane, see: (a) Saito, T.; Nakata, T. Org. Lett. 2009, 11, 113–
116. (b) Hennig, R.; Metz, P. Angew. Chem., Int. Ed. 2009, 48, 1157–
ꢀ
ꢀ
ꢀ
1159. (c) Pazos, G.; Perez, M.; Gandara, Z.; Gomez, G.; Fall, Y.
Tetrahedron Lett. 2009, 50, 5285–5287. (d) Furuta, H.; Hasegawa, Y.;
Mori, Y. Org. Lett. 2009, 11, 4382–4385. (e) Sletten, E. M.; Nakamura,
H.; Jewett, J. C.; Bertozzi, C. R. J. Am. Chem. Soc. 2010, 132, 11799–
11805. (f) Macıas, F. A.; Carrera, C.; Chinchilla, N.; Fronczek, F. R.;
´
Galindo, J. C. G. Tetrahedron 2010, 66, 4125–4132. (g) Furuta, H.;
Hasegawa, Y.; Hase, M.; Mori, Y. Chem.;Eur. J. 2010, 16, 7586–7595.
(4) (a) Hashimoto, N.; Aoyama, T.; Shioiri, T. Tetrahedron Lett.
1980, 21, 4619–4622. (b) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem.
Pharm. Bull. 1982, 30, 119–124.
(5) (a) Maruoka, K.; Concepcion, A. B.; Yamamoto, H. J. Org.
Chem. 1994, 59, 4725–4726. (b) Maruoka, K.; Concepcion, A. B.;
Yamamoto, H. Synthesis 1994, 1283–1290.
r
10.1021/ol302032w
Published on Web 08/17/2012
2012 American Chemical Society

Table 1. Ring Expansion Reaction of Ketone 1 with Various Silyldiazomethanes
entry
diazomethane
conditions
3 yield (%)
4 yield (%)
5 yield (%)
6 yield (%)
1
2a
2b
R = H
MeOH, rt, 45 min
3a
0
4a
4ac
49
5a
1a
6a
6b
4a
1d
2b
R = SiMe3
BF3 OEt2, MS 4 A, CH2Cl2,
3ac
3ac
3d
75
6
5b
5c
5d
13d
˚
3
ꢀ80 °C, 50 min,
then PPTS, CH2Cl2/MeOH
3
4
2c
R = SiMe2Ph
BF3 OEt2, MS 4 A, CH2Cl2,
79
57
4ac
4d
2
6
5
0
6c
0
1
˚
3
ꢀ80 °C, 3 h,
then PPTS, CH2Cl2/MeOH
˚
2d
R = Si(Oi-Pr)2Me
BF3 OEt2, MS 4 A, CH2Cl2,
6d
3
ꢀ80 °C, 1 h
a Spiro-epoxides 5a and 6a were isolated as a mixture. b The yield of the major product was previously reported in ref 8b. Complete byproduct
yields, however, are newly reported. c In entries 2 and 3, desilylated seven-membered ketone 3a and 4a (R = H) were isolated after PPTS treatment.
d Spiro-epoxides 5b and 6b were isolated as a mixture.
always (1) a seven-membered ketone that is generated
by migration of the less-hindered secondary carbon. Small
amounts of (2) a regioisomeric seven-membered ketone,
which is generated by migration of the sterically hindered
carbon, and (3) a spiro-epoxide formed by 3-exo cycliza-
tion are also produced as byproducts.
With regard to the mechanism of the ring expansion
reaction, both the Seto9 and Cushman10 groups proposed
that axial attack of TMS-diazomethane on six-membered
ketones is the first step in the ring expansion reaction. The
fact that only a small amount of epoxide arising from the
axial attack of TMS-diazomethane (3) was isolated in our
previous study,8c however, suggests that the major isomer
results from an equatorial attack on the ketone (1).
In addition, we are confident that seven-membered
ketones are generated from the equatorial attack of TMS-
diazomethane for the following reasons. First, in general,
BF3-promoted nucleophilic addition reactions of carbon
nucleophiles with six-membered ketones provide equatorial
adducts.11 Second, diazomethane approaches from the
equatorial side of ketones in the ring expansion reac-
tion without a Lewis acid.12 Therefore, we report here a
combined experimental and computational study of the
ring expansion reaction with silylated diazomethanes
to gain insight into the stereochemical course of the
reaction.
We selected the six-membered ketone 1 as a substrate
because its conformation is fixed as in the case of trans-
decalone. The first reaction was conducted with diazo-
methane 2a in methanol in the absence of a Lewis acid
(Table 1, entry1). Ketone4awasobtainedasa major prod-
uct generated by the migration of an electron-rich bond
according to the general trend of migration aptitude, as
well as a small amount of the mixture of spiro-epoxides 5a
and 6a in a 28:72 ratio.12a Ring expansion with TMS-
diazomethane 2b in the presence of BF3 OEt2 gave ketone
3
3a as a major product in 75% yield (entry 2).8b Careful
analysis of the byproducts led to the isolation of the
regioisomeric ketone 4a and two diastereomeric epoxides
5b and 6b in 6%, 13%, and 1%, respectively. The major
R-epoxide 5b came from the axial attack of TMS-diazo-
methane 2b, and the TMS group was located at the less
hindered side of the molecule.8c We next examined reac-
tions with a bulky silyldiazomethane 2c to increase the ratio
of the equatorial attack (entry 3). The yield of the seven-
membered ketones 3a was slightly increased, and the
R-epoxide 5c was obviously decreased, as expected. In
the reaction with bulkier diazomethane 2d, silylketones
3d and 4d were isolated following column chromatography
(entry 4). The configuration of the major ketone 3d was
(6) Dabrowski, J. A.; Moebius, D. C.; Wommack, A. J.; Kornahrens,
A. F.; Kingsbury, J. S. Org. Lett. 2010, 12, 3598–3601.
(7) The migratory aptitude of ring expansion reactions using diazo-
€
methanes varies depending on Lewis acids. For example: (a) Muller, E.;
€
Lurken, W.; Bauer, M. Tetrahedron Lett. 1962, 3, 775–778. (b) Mori, Y.;
Yaegashi, K.; Furukawa, H. Tetrahedron 1997, 53, 12917–12932. (c)
Kreuzer, T.; Metz, P. Eur. J. Org. Chem. 2008, 572–579.
(8) (a) Mori, Y.; Yaegashi, K.; Furukawa, H. J. Am. Chem. Soc.
1997, 119, 4557–4558. (b) Mori, Y.; Hayashi, H. Tetrahedron 2002, 58,
1789–1797. (c) Mori, Y.; Nogami, K.; Hayashi, H.; Noyori, R. J. Org.
Chem. 2003, 68, 9050–9060. (d) Sakai, T.; Sugimoto, A.; Mori, Y. Org.
Lett. 2011, 13, 5850–5853.
(9) Seto, H.; Fujioka, S.; Koshino, H.; Hayasaka, H.; Shimizu, T.;
Yoshida, S.; Watanabe, T. Tetrahedron Lett. 1999, 40, 2359–2362.
(10) Wang, Z.; Yang, D.; Mohanakrishnan, A. K.; Fanwick, P. E.;
Nampoothiri, P.; Hamel, E.; Cushman, M. J. Med. Chem. 2000, 43,
2419–2429.
(12) (a) Carlson, R. G.; Behn, N. S. J. Org. Chem. 1968, 33, 2069–2073.
(b) Jones, B.; Price, P. J. Chem. Soc. D: Chem. Commun. 1969, 1478–1479.
(13) Unfortunately, the stereochemistry of the regioisomer 4d could
not be determined unambiguously (see Supporting Information).
(11) (a) Trost, B. M.; Bonk, P. J. J. Am. Chem. Soc. 1985, 107, 1778–
1781. (b) Jenkins, T. J.; Burnell, D. J. J. Org. Chem. 1994, 59, 1485–1491.
(c) Crane, S. N.; Jenkins, T. J.; Burnell, D. J. J. Org. Chem. 1997, 62,
8722–8729.
Org. Lett., Vol. 14, No. 17, 2012
4565

determined to be trans based on the NOE results (Figure 1).13
We detected no R-epoxide and only a trace amount of
β-epoxide 6d. These results indicated that an exclusive
equatorial attack of 2d on ketone 1 occurred to generate
the ring expansion products 3d and 4d.14
Figure 2. ZPVE-corrected energy difference between (E)-10 and
(Z)-10 calculated at the B3LYP/6-31Gþ(d,p) level of theory.
Figure 1. Difference NOE correlation of 3d.
Scheme 2. Ring Expansion Reaction of 7 with
TMS-Diazomethane 2b
We also attempted a ring expansion reaction of ketone
7, which has an axial methyl next to the carbonyl group
(Scheme 2). The major product was trans-silylketone 8,
similar to entry 4 of Table 1, and only a trace amount of
spiro-epoxide 9 was detected. This finding supports the
preferential equatorial attack of TMS-diazomethane 2b on
the ketone 7.
Figure 3. Relative energy profiles of the ring expansion reaction
of 2-methylcyclohexanone with diazoethane promoted by BF3.
The ZPVE-correlated enegies calculated at the B3LYP/6-31Gþ(d,p)
level of theory. The conformational search of trans-14 was not
performed in detail. The indicated value (ꢀ49.9 kcal/mol) is one
of the possible stable conformations.
Scheme 3. Two Possible Pathways to Silylketone 3d
A, silyldiazomethane 2d approaches from the equatorial
side, and the silyl group is oriented antiperiplanar to the
carbonyl group after addition. In pathway B, silyldiazo-
methane 2d attacks from the axial side and the silyl group
aligns antiperiplanar to the tertiary carbon.
Based on our experimental results, the stereochemical
mechanism should be pathway A initiated by the equatorial
attack. Seto et al., however, previously proposed a contrast-
ing mechanism whereby TMS-diazomethane attacks a ke-
tone to avoid the steric repulsion between the silyl group and
the branched substituent.9 We therefore attempted to analyze
the two reaction pathways using a computational method.
The calculation was performed using GAMESS15 at
the B3LYP/6-31Gþ(d,p) level of theory. To simplify the
There are two possiblepathwaysfor the formation ofthe
trans diastereomer 3d, as shown in Scheme 3. In pathway
(14) For stereochemical mechanism of spiro-epoxide formation in
the ring expansion reaction of 1,6-anhydro-2-hexosuloses using TMS-
diazomethane, see: Kawai, T.; Isobe, M.; Peters, S. C. Aust. J. Chem.
1995, 48, 115–131.
(15) Schmidt, M. W.; Baldridge, K. K.; Boatz, J. A.; Elbert, S. T.;
Gordon, M. S.; Jensen, J. J.; Koseki, S.; Matsunaga, N.; Nguyen, K. A.;
Su, S.; Windus, T. L.; Dupuis, M.; Montgomery, J. A. J. Comput. Chem.
1993, 14, 1347–1363.
4566
Org. Lett., Vol. 14, No. 17, 2012

explained by the repulsion between BF3 and the methyl
group of diazoethane.
Scheme 4. Relative Energy of Transition States toward Four
Different Isomers via an Equatorial Attacka
We next compared the geometry of the migration transi-
tion states leading to four possible seven-membered ketones
to account for the high regio- and diastereoselectivity. As
shown in Scheme 4, eq-13 had the lowest energy among the
four isomers. The energy of transition state 15 was calcu-
lated to be more destabilizing by 3.3 kcal/mol compared to
that of eq-13 due to the steric repulsion between BF3 and the
methyl group of diazoethane. The regioisomeric transition
states 16 and 17 also had higher energies. This is due to
the steric interaction between the methyl and hydrogen or
the two methyls. Thus, these calculation data indicated
that trans-2,7-dimethylcycloheptanone is formed as a major
product via pathway A where diazoethane attacks from the
equatorial side of the carbonyl group.
In conclusion, we described a detailed stereochemical
mechanism of the BF3-promoted ring expansion reaction
of six-membered ketones with TMS-diazomethane based
onexperimentaland computationalmethods. The reaction
is initiated by the equatorial addition of TMS-diazomethane
to a ketone via a transition state in which the bulky silyl
group orients antiperiplanar to the carbonyl oxygen,
and migration of the less substituted carbon generates
a trans-seven-membered ketone with high regio- and
diastereoselectivity.
a The ZPVE-correlated energy (kcal/mol) calculated at the B3LYP/
6-31Gþ(d,p) level of theory.
calculation, diazoethane and 2-methylcyclohexanone were
used as model compounds for silyldiazomethane 2 and
ketone 1, respectively. There are two possible geometries of
BF3-coordinated 2-methylcyclohexanone 10 (Figure 2).
The calculated energy of (E)-10 was lower than that of
(Z)-10 by 5.2 kcal/mol. We then performed the following
calculations of energy profiles for the ring expansion re-
action on the assumption that BF3 is opposite from the
methyl group.
The energy profiles calculated for mixed complexes are
shown in Figure 3. The energies of pathway A were lower
than those of pathway B in both stages of addition and
migration. The maximum energy difference was estimated
to be 4.9 kcal/mol at the transition state of the migration
(13). This higher energy transition state ax-13 can be
Acknowledgment. This research was partially supported
by a Grant-in-Aid for Scientific Research (C) (21590029)
and a Grant-in-Aid for Young Scientists (B) (23790027)
from the Japan Society for the Promotion of Science (JSPS).
Supporting Information Available. Experimental pro-
1
cedures, spectroscopic data, and copies of H and 13C
NMR spectra of all new compounds. Cartesian coordi-
nates and energies of the optimized geometries; Cartesian
coordinates, energies, and imaginary frequencies of the
transition states. This material is available free of charge
via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
4567