Influence of substitution pattern on intramolecular alkylidene carbene insertion reactions

Article abstract of DOI:10.1016/S0040-4039(01)01853-6

A series of intramolecular alkylidene insertion reactions have been investigated. The nature of the substituents is demonstrated to have a dramatic effect on the outcome. In one example a novel rearrangement is observed.

Full text of DOI:10.1016/S0040-4039(01)01853-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8689–8692
Influence of substitution pattern on intramolecular alkylidene
carbene insertion reactions
Ahmed Bourghida, Vincent Wiatz and Martin Wills*
Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK
Received 23 August 2001; revised 25 September 2001; accepted 3 October 2001
Abstract—A series of intramolecular alkylidene insertion reactions have been investigated. The nature of the substituents is
demonstrated to have a dramatic effect on the outcome. In one example a novel rearrangement is observed. © 2001 Elsevier
Science Ltd. All rights reserved.
Previous work1 in our group has demonstrated that
ketone 1 is a good precursor for intramolecular alkyli-
dene carbene reactions. The carbenes may be generated
in a one-step process from a ketone and, provided a
five-membered product can be formed, the insertion
readily takes place into conveniently activated CꢀH
bonds (Scheme 1).2
It was observed that both reaction time and the amount
of phosphorus pentoxide employed were crucial for the
control of the ratios obtained (Table 1). The ratios
quoted refer to the minimum reaction time (15 min)
and lowest level of phosphorus pentoxide (15 mg/mg
substrate), under which conditions appreciable amounts
of 8 could be isolated. In contrast longer reaction times
(ca. 1 h) coupled with the use of an excess of phospho-
rus pentoxide favoured product 9 (thermodynamic
product) in essentially quantitative yield. It can be
concluded that compound 8 is the kinetic product and
an intermediate in the formation of 9.5
We are currently examining the application of this
methodology to the synthesis of a series of complex
target molecules. One potential application is to the
synthesis of five-membered ring sugars, which we con-
sidered might be prepared via the sequence illustrated
in Scheme 2.
The conversion from ester to ketone was achieved using
a two-step one-pot process. An excess of Grignard
reagent is required to arrive at the compounds 10a–d
and 11a–d.6 With a series of suitable materials in hand,
we were able to examine the insertion reactions of
derived alkylidene carbenes.
In order to examine the pivotal insertion reaction, we
required a suitable synthetic approach to a series of
derivatives of 3. In the event we established that com-
pounds 8a–d and 9a–d could both be synthesised via
the same procedure from diol 7a–d (Scheme 3).3,4
RO
RO
RO
RO
O
O
O
O
O
O
Ph
O
Ph
O
O
3
4
59%
O
2
1
RO
Scheme 1. Reagents and conditions: (i) TMSC(H)N2, n-BuLi,
DME/hexane.
RO
O
O
Keywords: alkylidene; carbene; insertion; intramolecular; rearrange-
ment.
5
HO
OH
* Corresponding author. Tel.: +44 24 7652 3260; fax: +44 24 7652
4112; e-mail: m.wills@warwick.ac.uk
Scheme 2.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01853-6

8690
A. Bourghida et al. / Tetrahedron Letters 42 (2001) 8689–8692
zyloxy group, suggesting that this position is electroni-
cally favoured over the methoxymethyl position.
R
R1
H
OMe
Product 15 may be formed via the insertion reaction of
a carbene formed by decomposition of the diazo inter-
mediate formed by addition of the neutral diazonium
reagent to the ketone, followed by trapping by the
b-methoxymethyl group, which is subsequently elimi-
nated (Scheme 7). A C- to O-trimethylsilyl migration
must also be a component of the mechanism, however,
the complete process is not fully understood at present.7
6a-d
O
i
HO
OH
R1
H
R
OMe
O
7a-d
Although we had anticipated that only the acyclic
substrates 10a–d would be likely to give insertion prod-
ucts, we considered it worthwhile to screen 11a in the
same reaction. As anticipated, no insertion products
were obtained from this attempted reaction (Scheme 8);
a complex mixture of products was formed.
ii
MeO
OMe
O
O
O
O
R1
or
H
R1
OMe
H
R
R
OMe
There was precedent for this reaction from the work of
Ohira et al. who used a C–H insertion of an alkylidene
carbene in their synthesis of (−)-Neplanocin A (Scheme
9).8 The insertion was performed on intermediate 16 to
give cyclopentene 17 containing a cis-fused bicyclic
system.
O
O
9a-d
8a-d
iii
iii
MeO
O
O
O
OMe
O
R1
H
R1
The difference can be explained by the fact that product
H
R
R
17 contains
a readily-accessibly cis-ring junction,
whereas the same reaction on 11d must lead to a
O
11a-d
O
product bearing a trans-junction.
10a-d
We have concluded that alkylidene carbene may be
unable to reach the bridging methylene group due to
the strain involved in achieving this. We did not
attempt the insertion reactions of compounds 11b and
11c, however, we evaluated the reaction of 11d with
lithiated TMS–diazomethane in order to determine
whether the carbene intermediate could react with the
methylene of the benzyl protecting group to give a
trans-fused bicyclic product. However, no insertion
product was formed (Scheme 7).
Scheme 3. Reagents and conditions: (i) Super Admix(a); (ii)
dimethoxymethane, dichloromethane, P2O5; (iii) N,O-
dimethylhydroxylamine·HCl, MeMgBr, THF.
Dihydrofurans 12 and 13 resulted from the successful
insertion reactions of compounds 10a and 10c (Scheme
4). In the case of 12, a product was formed as a single
diastereoisomer, which has been assigned as cis on the
basis of a positive NOE effect between the C2 and C5
protons of the dihydrofuran ring. In contrast, the
attempted insertion reaction using 10b gave a complex
mixture of unidentified products (Scheme 5).
In conclusion, we have demonstrated that the exact
substitution pattern of a substrate has a significant
effect upon the same alkylidene carbene insertion reac-
tion. It appears that the formation of five-membered
rings will always be favoured since this is a kinetic
reaction, and that the C–H insertion site benefits from
activation through the proximity of heteroatoms like
oxygen. We intend, in the near future, to investigate
further on the reasons why there is selectivity when
more than one site is possible. Although we have not
The benzyl-substituted compound 10d also did not give
any of the expected dihydrofuran products; instead
compounds 14 and 15 were obtained (Scheme 6), the
former as a 1:1 isomeric mixture and the latter as what
appeared to be a single diastereoisomer. Product 14 is
quite clearly the result of the insertion of the alkylidene
carbene into the methylene group adjacent to the ben-
Table 1. Synthesis of substrates for insertion reactions
Series
R
R%
7 (%)a
Ratio 8:9b
8 (%)a
10 (%)a
11 (%)a
a
b
c
Ph
Me
H
H
H
Me
H
99
74
80
92
4.5:1
5:1
3:1
81
84
57
56
62
63
68
45
30
–
–
d
CH2OBn
3:1
26
a Isolated yield.
b Under conditions of minimal time and catalyst (P2O5) loading.

A. Bourghida et al. / Tetrahedron Letters 42 (2001) 8689–8692
8691
cooled once again to −60°C and the ketone (1 mmol) in
dimethoxyethane (20 mL) was added. The reaction was
stirred for 4 h and allowed to warm to room tempera-
ture over this time. The reaction was quenched with
water, extracted with EtOAc, filtered, and the com-
bined extracts were washed with water. The residue was
then dried over magnesium sulfate and concentrated in
a rotavaporator. The product was purified by flash
chromatography (EtOAc, hexane).
MeO
OMe
MeO
O
O
O
O
i
OMe
H
H
H
40%
Ph
H
Ph
O
12 (single isomer)
10a
OMe
MeO
MeO
O
O
O
O
i
OMe
Me
12: wmax (neat)/cm−1 2939, 2893, 2825, 2761, 1599, 1451,
1371, 1035, 747, 690; Rf (20% EtOAc/hex) 0.42; lH (300
MHz, CDCl3) 7.20–7.32 (5H, m, aryl H), 5.50 (1H, d, J
3.9, ꢁCH-), 5.33 (1H, s, Ph-CH-CH-O-), 4.88 (1H, s,
-O-CH-OCH3), 4.69 (1H, d, J 3.9, Ph-CH-CH-O-), 4.51
(2H, AB, JAB 6.6, -O-CH2-OCH3), 3.29 (3H, s, -O-CH-
OCH3), 3.23 (3H, s, -O-CH2-OCH3), 1.67 (3H, s, -CH3);
lC (300 MHz, CDCl3) 163.9, 143.0, 138.5, 128.6, 128.4,
128.2, 123.7, 109.1, 94.9, 89.9, 78.6, 56.1, 54.0.
85%
Me
O
10c
13 (1:1 isomeric
mixture)
Scheme 4. Reagents and conditions: (i) TMSC(H)N2, n-BuLi,
DME/hexane.
OMe
MeO
O
O
complex
mixture
H
H
13 (isomer 1): wmax (neat)/cm−1 2932, 2869, 1673, 1382,
1442, 1037, 844; Rf (20% EtOAc/hex) 0.33; lH (300
MHz, CDCl3) 5.61 (1H, t, J 1.5, ꢁCH-), 5.48 (1H, t, J
1.5, -O-CH-OCH3), 4.64 (2H, AB, JAB 7.8, -O-CH2-
OCH3), 3.52 (2H, s, -CH2-O-CH2-OCH3), 3.39 (3H, s,
-OCH3), 3.36 (3H, s, -OCH3), 1.77 (3H, t, J 1.5, ꢁC-
CH3), 1.33 (3H, s, -O-C-CH3), lC (300 MHz, CDCl3)
148.1, 122.1, 107.9, 97.3, 90.2, 72.1, 56.2, 54.6, 23.1,
12.5.
Me
O
10b
Scheme 5. Reagents and conditions: (i) TMSC(H)N2, n-BuLi,
DME/hexane.
OMe
MeO
O
O
H
H
13 (isomer 2): wmax (neat)/cm−1 2930, 2876, 1668, 1382,
1444, 1037, 844; Rf (20% EtOAc/hex) 0.40; lH (300
MHz, CDCl3) 5.55 (1H, t, J 1.5, ꢁCH-), 5.47 (1H, t, J
1.5, -O-CH-OCH3), 4.68 (2H, AB, JAB 7.0, -O-CH2-
OCH3), 3.54 (2H, AB, JAB 10.2, -CH2-O-CH2-OCH3),
3.40 (3H, s, -OCH3), 3.37 (3H, s, -OCH3), 1.79 (3H, t,
J 1.3, ꢁC-CH3), 1.31 (3H, s, -O-C-CH3); lC (300 MHz,
CDCl3) 147.2, 121.7, 107.8, 97.2, 89.8, 73.6, 55.6, 55.2,
22.3, 12.8.
BnO
10d
O
i
ratio 14:15 1.5:1
OMOM
OMOM
OBn
O
BnO
+
OTMS
MOMO
14 (isomer 1): wmax (neat)/cm−1 2946, 2890, 2823, 2750,
1028, 919, 845, 698; Rf (20% EtOAc/hex) 0.24; lH (300
MHz, CDCl3) 7.22–7.38 (5H, m, aryl H), 5.68 (1H, m,
ꢁCH-), 4.89 (1H, d, JAB 7.5, O-CH2-OCH3), 4.76 (2H,
s, Ph-CH2-O-), 4.71 (1H, d, JAB 7.5, O-CH2-OCH3),
4.54 (2H, AB, JAB 15, -CH(O-CH2-OCH3)), 4.41–4.45
(1H, m, Ph-CH2-O-CH-CH(O-CH2-OCH3)-), 4.07 (1H,
t, J 6.3, -CH(O-CH2-OCH3)), 3.43 (6H, s, 2×OCH3),
1.80–1.82 (3H, m, -CH3); lC (300 MHz, CDCl3) 146.3,
128.7, 128.2, 127.9, 126.3, 96.9, 96.5, 86.1, 82.7, 78.1,
70.9, 56.2, 56.1, 14.9.
14 (1:1 mixture) 39%
15, 24%
Scheme 6. Reagents and conditions: (i) TMSC(H)N2, n-BuLi,
DME/hexane.
yet measured enantiomeric excesses of any product, the
use of the Sharpless dihydroxylation in the first step
permits potential access to either enantiomeric product
in high e.e.
Example procedure for insertion reaction and selected
spectroscopic data
14 (isomer 2): wmax (neat)/cm−1 2947, 2890, 2822, 2750,
1045, 920, 844, 698; Rf (20% EtOAc/hex) 0.40; lH (300
MHz, CDCl3) 7.25–7.39 (5H, m, aryl H), 5.59–5.63
(1H, m, ꢁCH-), 4.85 (1H, d, JAB 8.1, O-CH2-OCH3),
4.78 (2H, AB, JAB 9.0, Ph-CH2-O-), 4.71 (1H, d, JAB
8.1, O-CH2-OCH3), 4.60 (2H, d, J 2.4, -CH(O-CH2-
OCH3)), 4.29–4.31 (2H, m, -CH-CH(O-CH2-OCH3)-),
4.22 (1H, t, J 3.6, -CH(O-CH2-OCH3)), 3.43 (3H, s,
-OCH3), 3.42 (3H, s, -OCH3), 1.78–1.82 (3H, m, -CH3);
Trimethylsilyldiazomethane (2.0 M in hexane, 2 equiv.)
was stirred in 1,2-dimethoxyethane (20 mL/mmol of
olefin) at −78°C. To this, n-butyllithium (2.5 M in
hexane, 2 equiv.) was added carefully over 10 min.
After 10 min stirring at −78°C, the cooling bath was
removed and the reaction was allowed to warm until a
clear solution was observed (−10°C). The reaction was

8692
A. Bourghida et al. / Tetrahedron Letters 42 (2001) 8689–8692
lC (300 MHz, CDCl3) 143.3, 128.7, 128.1, 127.9, 127.1,
96.4, 96.1, 88.2, 86.8, 86.2, 71.1, 56.1, 56.0, 14.7.
OMe
OMe
MeO
MeO
O
O
O
O
H
H
H
H
15: wmax (neat)/cm−1 2954, 2880, 2823, 1252, 1026, 920,
842, 698; Rf (20% EtOAc/hex) 0.54; lH (300 MHz,
CDCl3) 7.13–7.22 (5H, m, aryl H), 4.44 (2H, AB, JAB
8.1, Ph-CH2-O-), 4.42 (2H, AB, JAB 16.2, Ph-CH2-O-
CH2-), 4.27–4.34 (1H, td, J 4.5, 6.0, Ph-CH2-O-CH2-
CH-O-), 3.66 (1H, d, J 4.2, -CH-O-CH2-OCH3), 3.58
(2H, AB, JAB 10.8, -CH-O-CH2-OCH3), 3.50 (2H, m,
-O-CH2-C-O-Si-(CH3)3), 3.22 (3H, s, -OCH3), 1.24 (3H,
s, -CH3), 0.00 (s, 9H, -Si-(CH3)3); lC (300 MHz, CDCl3)
138.4, 128.7, 128.3, 128.0, 97.8, 85.3, 83.6, 80.3, 76.9,
73.9, 69.4, 56.7, 20.1, 2.5.
BnO
BnO
10d
O
O
TMS
N2
+ TMSC(N2)H
H
OMe
OMe
H
OBn
OBn
O
O
..
H
OTMS
OTMS
MOMO
MOMO
Acknowledgements
OBn
proton
abstraction
We thank the EPSRC for a project studentship (to
A.B.), Dr. B. Stein of the EPSRC MS service at
Swansea, and We wish to acknowledge the use of the
EPSRCs Chemical Database Service at Daresbury.9
O
H
15
OTMS
MOMO
Scheme 7. Possible mechanism of formation of compound 15.
References
O
O
1. Walker, L. F.; Connolly, S.; Wills, M. Tetrahedron Lett.
1998, 39, 5273.
no reaction
H
R'
2. Miwa, K.; Aoyama, T.; Shioiri, T. Synlett 1994, 461.
3. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino,
G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.;
Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org.
Chem. 1992, 57, 2768.
R
O
11a/11d
Scheme 8. Reagents and conditions: (i) TMSC(H)N2, n-BuLi,
DME/hexane.
4. Wang, Z.; Kolb, H. C.; Sharpless, K. B. J. Org. Chem.
1994, 59, 5104.
5. Fuji, K.; Nakano, S.; Fujita, E. Synthesis 1975, 276.
6. Huang, T.; Mahmood, K.; Mathis, C. A. J. Labelled
Compd. Radiopharm. 1999, 42, 949.
TrO
O
TrO
OTBS
OTBS
1
7. Examination of crude H NMR spectra from the insertion
i
reactions of 10a and 10c suggested that compounds
analogous to 15 may also have been formed in low yield
(<5%) in these reactions.
O
O
O
O
55%
16
17
8. Ohira, S.; Sawamoto, T.; Yamato, M. Tetrahedron Lett.
1995, 36, 1537.
Scheme 9. Reagents and conditions: (i) TMSC(H)N2, n-BuLi,
THF.
9. Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J. Chem.
Inf. Comput. Sci. 1996, 36, 746–749.