Effect of solvent polarity on N-H insertion versus rearrangement of alkylidene carbenes

Article abstract of DOI:10.1016/j.tetlet.2005.07.015

Alkylidene carbenes, when generated from o-aminobenzophenones and lithiated trimethylsilyldiazomethane, give a mixture of alkyne (by rearrangement) and indole (by N-H insertion). It has been found that this ratio of indole to acetylene shows a linear dependence on the polarity of the ethereal solvent.

Full text of DOI:10.1016/j.tetlet.2005.07.015

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6045–6047
Effect of solvent polarity on N–H insertion versus
rearrangement of alkylidene carbenes
Douglass F. Taber* and Raymond A. Plepys
Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA
Received 13 January 2005;revised 2 July 2005;accepted 5 July 2005
Available online 26 July 2005
Abstract—Alkylidene carbenes, when generated from o-aminobenzophenones and lithiated trimethylsilyldiazomethane, give a mix-
ture of alkyne (by rearrangement) and indole (by N–H insertion). It has been found that this ratio of indole to acetylene shows a
linear dependence on the polarity of the ethereal solvent.
Ó 2005 Elsevier Ltd. All rights reserved.
Table 1. Conversions and reaction yields for Scheme 1
The reaction of a ketone with the lithium salt of trimeth-
Solvent/ET value6
% Yield
Indole/alkyne (3/4)
ylsilyldiazomethane (TMSDM) has been shown to be an
efficient way to generate the corresponding alkylidene
carbene.1–3 Using this procedure, we studied4 the reac-
tions of the 2,2-diaryl alkylidene carbene 2 from 2-
aminobenzophenone 1. We have observed that the ratio
of the two products 3 and 4 (Scheme 1) is linearly depen-
dent on the polarity of the reaction solvent. Our results
are summarized in Table 1.3
Entry
1
2
3
4
5
THF (37.4)
90
62
93
97
82
0.70
0.83
0.51
0.19
0.41
Glyme (38.2)
1,4-Dioxane (36.1)a
Et2O (34.5)
MTBE (34.7)
a Solvent was a blend of 90% dioxane and 10% THF due to the high
freezing point of pure 1,4-dioxane. The ET value was interpolated
between the two solvents.
Although, there was no discernible relationship between
product ratios and the dielectric constant or dipole
moment of these solvents, we found a dependence of
the ndole/acetylene ratio (3/4) on solvent polarity as
measured by the solvent solvatochromatic shift
ET(30)5,6 values. Figure 1 shows a graphical representa-
tion of the product ratios versus ET(30)6 value. There
was more than a fourfold change in product ratio over
the solvent range studied and a seemingly linear rela-
tionship of the product ratio with solvent polarity.
O
C
Li TMSDM
Ph
Ph
-40 oC
THF
NH2
Ph
NH2
Ph
1
2
There are few literature reports that deal quantitatively
with carbene reactions as a function of solvent polarity.
Most of these studies contend with a wide variety of pos-
sible reactions such as C–H insertion, 1,2-hydrogen
shift, and alkyl/aryl rearrangement. Jones and Buck10
report an increase in methyl migration for tert-butylcar-
bene to form 2-methyl-2-butene versus C–H insertion to
form 1,1-dimethylcyclopropane as solvent polarity is
increased. Gilbert and Blackburn11 also reports
increased rearrangement versus C–H insertion for the
self-reaction of a 2-methyl-2-carbamoyl alkylidene car-
bene. Platz and Jones12 reports no effect of solvent
+
N
H
NH2
3
4
37%
53%
Scheme 1.
Keywords: Diphenylacetylenes;Indoles;Intramolecular N–H insertion;
Carbene rearrangement;Solvent polarity.
Corresponding author. Tel.: +1 302 831 2433;fax: +1 302 831
6335;e-mail: taberdf@udel.edu
*
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.015

6046
D. F. Taber, R. A. Plepys / Tetrahedron Letters 46 (2005) 6045–6047
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
glyme
THF
dioxane
MTBE
ether
34
34.5
35
35.5
36
36.5
37
37.5
38
38.5
Solvent ET value
Figure 1. Plot of solvent polarity versus indole/acetylene ratio of o-aminobenzophenone 1.
Ph
Ph
Ph
Ph
Ph
Ph
6
7
8
Ph
Ph
Ph
5s
5t
triplet
RO
Ph
Ph
R-OH
singlet
Ph
9
Scheme 2.
polarity on the reaction rate of phenylchlorocarbene
with pyridine. Hadad and co-workers13 have also inves-
tigated the effect of several solvents and substituents on
the energy gap between singlet and triplet states of
phenyl(carbomethoxy)carbene using time resolved IR
spectroscopy. Tamioka et al.14 reports little effect of sol-
vent polarity (cyclohexane, benzene, and acetonitrile) on
the competitive O–H insertion reaction of monophen-
ylcarbene in MeOH/2-PrOH and MeOH/t-BuOH mix-
tures. However, he does note a very specific solvent
effect on these reactions favoring MeOH O–H insertion
in the presence of 1,4-dioxane (vs ether, THF, 1,3-dioxo-
lane etc.).
the singlet carbene, and that the effect we are observing
is due to a solvation-induced change in the hybridization
of that carbene.
The results reported here describe a nicely balanced
system where only two major reactions occur—intra-
molecular N–H insertion and 2,1-aryl rearrangement
(without atomic labeling it is not possible to tell which
aryl group migrates—phenyl or 2-aminophenyl). It
may be of interest to explore the effect of aromatic
substituents16 on the selectivity of the intermediate
carbene.17
The only report to quantify the effect of solvent polarity
as measured by ET values on carbene reactions is by
Garcia-Garibay et al.15 In a study focused (Scheme 2)
on the reactions of 1,2-diphenylbutylene carbine he
ascribed product 6 from 1,2-hydrogen shift and product
7 from intermolecular O–H insertion to the singlet state,
while the triplet state led to phenyl rearrangement to
give 8 and C–H insertion to give cyclopropane 9.
Grouping these reactions, he observed a linear relation-
ship between the ratio of triplet/singlet products and sol-
vent polarity as measured by ET values.
Acknowledgement
We thank the NIH (GM60287) for support of this work.
References and notes
1. Taber, D. F.;Yu, H. J. Org. Chem. 1997, 62, 1687–
1690.
2. Ohira, S.;Noda;Mizobata;Yamato, M. Tetrahedron Lett.
1995, 36, 1537.
3. A recent publication reports a similar mixture: Miyagi, T.;
Hari, Y.;Aoyama, T. Tetrahedron Lett. 2004, 45, 6303–
6305. Aoyama and co-workers observed that the N-tosyl
derivative of 1 was cleanly converted to the N-tosyl
derivative of 2 when treated with lithiated TMSDM in
THF.
We speculate that, we are observing a similar effect to
that reported by Garcia-Garibay et al.15 as the ratio of
3:4 increases with increasing solvent polarity. However,
we think it likely that both of our products stem from

D. F. Taber, R. A. Plepys / Tetrahedron Letters 46 (2005) 6045–6047
6047
4. Representative procedure (Table 1, entry 5). To a solution
of 1.0 mmol TMSDM (0.5 mL of 2.0 M solution in
hexane) in 10 mL dry MTBE at À40 °C under N2
1.00 mmol n-butyl lithium (0.50 mL of 2.0 M solution in
hexane) was added. This mixture was stirred and allowed
to warm to 0 °C (until condensed ice melted on the outside
of the flask). The solution was then cooled to À40 °C and
a solution of 0.10 g (0.5 mmol) 2-aminobenzophenone in
10 mL dry MTBE was added dropwise over 1 h. The
mixture was stirred at À40 °C for 2 h and then was
warmed slowly to room temperature. The reaction mixture
was partitioned between sequentially satd aqueous NH4Cl
and satd brine. The combined organic extract was dried
(MgSO4) and filtered. To this solution 50 mg of anthra-
nilonitrile (internal standard) was added. The solution was
then diluted to 100 mL with hexane for analysis by HPLC
(normal phase silica, 15% MTBE in hexane eluent, UV
detection at 281 nm and calibrated for response factors
with anthranilonitrile internal standard). Authentic pro-
ducts were isolated by flash column chromatography and
identities were confirmed by NMR and mp from the
literature data for 3-phenyl-5-nitroindole,7 3-phenylin-
dole,8 and 2-aminodiphenylacetylene.9
9. Hiroya, K.;Itoh, S.;Sakamoto, T. J. Org. Chem. 2004, 69,
1126–1136.
10. Jones, M., Jr.;Buck, R. T. Tetrahedron Lett. 1998, 39,
2277–2280.
11. Gilbert, J. C.;Blackburn, B. K. J. Org. Chem. 1986, 51,
3656–3661.
12. Platz, M. S.;Jones, M. B. J. Org. Chem. 1991, 56, 1694–
1695.
13. Geise, C. M.;Wang, Y.;Mykhaylova, O.;Frink, B. T.;
Toscano, J. P.;Hadad, C. M. J. Org. Chem. 2002, 67,
3079–3088.
14. Tamioka, H.;Ozaki, Y.;Izawa, Y. Tetrahedron 1985, 21,
4987–4993.
15. Garcia-Garibay, M. A.;Theroff, C.;Shin, S. H.;Jernelius,
J. Tetrahedron Lett. 1993, 34, 8415–8418.
16.
O
Ph
O N
2
Li TMSDM
o
O N
Ph
NH
2
-40
C
2
N
THF
70%
H
10
11
The reaction of 2-amino-5-nitrobenzophenone 10 gave
only 3-phenyl-5-nitroindole 11 in 70% yield under the
reaction conditions outlined above.
5. Reichardt, C. Pure Appl. Chem. 1982, 54, 1867–1884.
6. Reichardt, C. Chem. Rev. 1994, 94, 2319.
7. Erra-Balsells, R.;Frasca, A. R. Magn. Reson. Chem. 1989,
27, 134–137.
8. Morales-Rios, M. S.;Espineira, J.;Joseph-Natan, P.
Magn. Reson. Chem. 1987, 25, 377–395.
17. For recent reviews of indole syntheses, see: (a) Gribble,
G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045–
1075;Pindur, U.;Adam, R. J. Heterocycl. Chem. 1988,
25, 1–8.