Pentamethylcyclopentadienide in organic synthesis: Nucleophilic addition of lithium pentamethylcyclopentadienide to aromatic aldehydes and carbon-carbon bond cleavage of the adducts affording the parent aldehydes

Article abstract of DOI:10.1016/j.tetlet.2005.05.094

Treatment of aromatic aldehyde with lithium pentamethylcyclopentadienide provided the corresponding carbinol in excellent yield. The carbinol returns to the parent aldehyde and pentamethylcyclopentadiene upon exposure to an acid or due to heating. The com

Full text of DOI:10.1016/j.tetlet.2005.05.094

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4831–4833
Pentamethylcyclopentadienide in organic synthesis:
nucleophilic addition of lithium pentamethylcyclopentadienide
to aromatic aldehydes and carbon–carbon bond cleavage of
the adducts affording the parent aldehydes
Kazunari Yagi, Hideki Yorimitsu* and Koichiro Oshima*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto-daigaku Katsura,
Nishikyo-ku, Kyoto 615-8510, Japan
Received 25 April 2005; revised 19 May 2005; accepted 20 May 2005
Abstract—Treatment of aromatic aldehyde with lithium pentamethylcyclopentadienide provided the corresponding carbinol in
excellent yield. The carbinol returns to the parent aldehyde and pentamethylcyclopentadiene upon exposure to an acid or due to
heating. The combination of the two reactions can represent a protection of aromatic aldehyde.
Ó 2005 Elsevier Ltd. All rights reserved.
Table 1. Nucleophilic addition of Cp*Li to aromatic aldehydes and
carbon–carbon bond cleavage of the adducts affording the parent
aldehydes and Cp*H
One cannot overestimate the importance of pentamethyl-
cyclopentadienide (Me5C5À, Cp*À) as a ligand in transi-
tion metal chemistry.1,2 Its steric bulkiness as well as
Cp*Li (1.2 equiv)
THF, —20 ºC, 1 h
then H2O
delocalized 6p-electron system provides coordinated
metals with a unique environment and, as a result,
the complexes with interesting reactivity, enhanced solu-
bility, and crystallizability. In the field of organic synthe-
sis, Cp*À serves as a ligand of transition metal catalysts.
However, there are few reports on useful reactions of
Cp*À itself.3 Here we report an example, wherein Cp*À
adds to aromatic aldehydes to temporarily protect the
aldehyde moiety, taking advantage of formally revers-
ible carbon–carbon bond formation/cleavage.4
OH
Me
Me
Me
O
Ar
H
Ar
Me
CCl3COOH (0.10 equiv)
CH2Cl2, 25—30 ºC, 0.25—1.5 h
1
2
Me
Entry
Ar
From 1 to 2
(%)
From 2 to 1
(%)
1
2
3
4
5
6
7
8
p-BrC6H4 (a)
2-C10H7 (b)
95
88
85
87
95
98
84
97
92
87
87
91
79
87
93
69
p-PhC(@O)C6H4 (c)
p-MeOC(@O)C6H4 (d)
p-NCC6H4 (e)
Nucleophilic addition of Cp*À to aromatic aldehydes
proceeded in excellent yield.5 Treatment of p-bromo-
benzaldehyde (1a, 2.0 mmol) with Cp*Li (2.4 mmol,
p-BuOC6H4 (f)
p-iPrC(@O)C6H4 (g)
o-MeOC6H4 (h)
n
generated from BuLi and Cp*H) in THF at À20 °C
for 1 h afforded the corresponding carbinol 2a in 95%
isolated yield (Table 1, entry 1, from 1 to 2). Higher tem-
perature led to the concurrence of a side reaction,
Meerwein–Ponndrof–Verley reduction/Oppenauer oxi-
dation to form p-bromobenzyl alcohol and p-Br–
C6H4C(@O)Cp*. Use of methylmagnesium bromide to
abstract the acidic proton of Cp*H also enhanced the
reduction/oxidation side reaction. The attempted nucleo-
philic addition reaction resulted in no or little conver-
sion under Cs2CO3/DMSO, KN(SiMe3)2/THF, or
NaN(SiMe3)2/THF deprotonation conditions.
Keywords: Pentamethylcyclopentadiene; Nucleophilic addition;
Carbon–carbon bond cleavage; Protection; Aldehydes.
*
Corresponding authors. Tel.: +81 75 383 2441; fax: +81 75 383 2438;
e-mail addresses: yori@orgrxn.mbox.media.kyoto-u.ac.jp; oshima@
orgrxn.mbox.media.kyoto-u.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.094

4832
K. Yagi et al. / Tetrahedron Letters 46 (2005) 4831–4833
A variety of aromatic aldehydes underwent the nucleo-
philic addition (Table 1, from 1 to 2). The reaction
was highly chemoselective. Keto (entries 3 and 7), ester
(entry 4), and cyano (entry 5) moieties did not interfere
with the reaction. Despite its steric factor, ortho-substi-
tution did not retard the reaction (entry 8). Unfortu-
nately, the reaction with dodecanal failed to yield a
satisfactory amount of the corresponding adduct (ca.
50% yield), instead furnishing several aldol adducts. Dif-
ferent from the reactions with 1c and 1g, enolization of
p-formylacetophenone took place to yield the expected
adduct in less than 30% yield.
Ar
Me
Me
Me
Me
Ar
Me
Me
Me
thermal
H
+
2
2
O
O
+
H
H
H
Me
Me
Me
Ar
Ar
Me
Me
OH
Me
Me
acidic
Me
O +
H
Me
or
H
+
H
Me
Me
Me
Me
Scheme 2.
Carbinols 2 were unstable under acidic conditions and
were transformed into the parent aldehydes via carbon–
carbon bond cleavage.6,7 Treatment of 2a with
10 mol % of trichloroacetic acid in dichloromethane at
25–30 °C for 1.5 h provided 1a in 92% isolated yield (en-
try 1, from 2 to 1). Concomitant recovery of a quantita-
tive amount of Cp*H is advantageous since Cp*H is
costly. Other acids such as trifluoroacetic acid, camphor-
sulfonic acid monohydrate, p-toluenesulfonic acid mono-
hydrate also effected the carbon–carbon bond cleavage
under the otherwise same reaction conditions, although
the yields of 1a were lower by ca. 20% because of several
unidentified by-products. Use of acetic acid promoted the
elimination very slowly. Silica gel in dichloromethane did
not work at all. In polar coordinating solvents such as
THF and methanol, acid-catalyzed cleavage was not ob-
served. Under the standard reaction conditions, all the
carbinols 2 were transformed into the parent aldehydes
without any difficulty (Table 1, from 2 to 1).
on the acid-catalyzed cleavage can be rationalized by
specific acid catalysis. To clarify the reaction course, fur-
ther investigation is necessary.
The utility of the Cp* group as a protective group is
demonstrated in Scheme 3. After Cp* had masked the
aldehyde moiety of 1c in situ, the keto group was sub-
jected to nucleophilic addition reaction with phenyl-
lithium to afford diol 4a. The crude oil was exposed to
the acidic conditions to produce hydroxy aldehyde 5a
in 85% overall yield. Chemoselective reduction and allyl-
ation were also successful to furnish 5b and 5c, respec-
tively.9,10 Attempted Wittig reaction of
3
with
CH2@PPh3 failed, and the methylenation of the alde-
hyde moiety that must be masked was partly observed.
Instead, addition of trimethylsilylmethyllithium to 3 fol-
lowed by acid-catalyzed olefination in aqueous THF
yielded the carbinol 6. Treatment of 6 under the depro-
tection conditions afforded 7 in 81% overall yield. All
the procedures proceeded so cleanly that no purification
of the intermediates such as 4 and 6 was necessary.
A similar carbon–carbon bond cleavage was observed in
the absence of acid. Heating 2a and 2e in toluene at
reflux provided aldehydes 1a and 1e in 88% and 93%
yields, respectively (Scheme 1). Electron-rich carbinol
2f required a higher temperature to return efficiently to
1f in boiling xylene. Complete conversion of 2f in reflux-
ing toluene took more than 20 h, albeit the yield was
quantitative.
The in situ protection made preparation of
formyl-substituted phenyllithium equivalent feasible
a
(Scheme 4). Nucleophilic addition of Cp*Li to 1a fol-
a) PhLi,
OLi
b) LiAlH4,
O
A retro-carbonyl-ene mechanism can rationalize the
fragmentation reaction (Scheme 2).8 The thermal reac-
tion would proceed via a concerted mechanism although
thermal retro-carbonyl-ene reactions generally require
higher temperature, most of which were performed in
a gas phase.8e The reaction temperatures used herein
are extremely low as being a temperature for a retro-car-
bonyl-ene reaction. Since a number of acids catalyze car-
bonyl-ene reactions, trichloroacetic acid can lower the
barrier of activation of the present retro-reaction based
on the principle of microscopic reversibility. Alterna-
tively, protonation at the Cp* group can facilitate
the carbon–carbon bond cleavage. The solvent effect
c) CH2=CHCH2MgCl,
or d) Me3SiCH2Li
Cp*
Cp*Li
H
Ph
Ph
THF
—20 ºC
1c
O
O
3
OH
O
Cp*
H
CCl3COOH (0.10 equiv)
Ph
Ph
CH2Cl2, 25—30 ºC, 1 h
for 4a—c
4a—d HO
R
HO R
85% R = Ph (5a)
64% R = H (5b)
for 4d (R = Me3SiCH2)
80% R = CH2=CHCH2 (5c)
H2SO4
THF/H2O
0 ºC, 30 min
O
OH
OH
Ar
2
O
Cp*
1a (88%, 0.5 h, in toluene)
1e (93%, 3 h, in toluene)
1f (97%, 3 h, in xylene)
CCl3COOH (0.10 equiv)
CH2Cl2, 25—30 ºC, 30 min
H
Cp*
Ph
Ph
H
Ar
solvent,
reflux
1
6
81%
7
Scheme 1.
Scheme 3.

K. Yagi et al. / Tetrahedron Letters 46 (2005) 4831–4833
4833
3. Reactions of pentamethylcyclopentadienide to form a new
Cp*–C bond: (a) Kohl, F. X.; Jutzi, P. Chem. Ber. 1987,
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OLi
OLi
Cp*Li
2 tBuLi
—78 ºC
Cp*
Cp*
1a
THF
—20 ºC
Br
Li
8
OH
Cp*
PhCHO
CCl3COOH (0.10 equiv)
CH2Cl2, 25—30 ºC, 30 min
5b
88%
—78 ºC
then H2O
Ph
4b
OH
Scheme 4.
lowed by bromine–lithium exchange furnished aryl-
lithium 8. The lithium reagent 8 could be trapped with
benzaldehyde to yield crude diol 4b. Subsequent
removal of Cp*H afforded 5b in 88% overall yield.
4. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; John Wiley & Sons: New
York, 1999.
5. Nucleophilic addition of Cp*À to acetaldehyde was
reported as the sole example. See Ref. 3f.
In summary, pentamethylcyclopentadiene or its anionic
form has now participated in organic synthesis as a new
ÔreagentÕ, taking advantage of the facile cleavage of the
carbon–carbon bond, specifically the Cp*–CAr(H)OH
bond. The in situ protection of an aldehyde moiety
has realized a new chemoselective reaction and genera-
tion of an organometallic reagent having a masked alde-
hyde group.
6. Base-mediated fragmentation reaction of LiOCHCp* to
2
produce Cp*Li and Cp*CHO was reported as a side
reaction. Jutzi, P.; Mix, A.; Lindermeier, T.; Stammler,
H.-G.; Neumann, B. Chem. Ber. 1994, 127, 107–112.
7. Acid-catalyzed fragmentation of Cp*COCH3 with the aid
of ethylene glycol was observed. Burger, U.; Delay, A.;
Mazenod, F. Helv. Chim. Acta 1974, 57, 2106–2111.
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1980, 13, 426–432; (b) Snider, B. B. In Comprehensive
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Pergamon Press: Oxford, 1991; Vol. 2, Chapter 2.1; (c)
Mikami, K.; Shimizu, M. Chem. Rev. 1992, 92, 1021–1050;
(d) Paderes, G. D.; Jorgensen, W. L. J. Org. Chem. 1992,
Acknowledgments
This work was supported by Grants-in-Aid for Scientific
Research, Young Scientists, and COE Research, from
the Ministry of Education, Culture, Sports, Science
and Technology, Government of Japan.
´
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M. T.; Wenderoth, B.; Peter, R. J. Chem. Soc., Chem.
Commun. 1983, 406–408; (b) Reetz, M. T.; Wenderoth, B.
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Supplementary data
Supplementary data including experimental details and
characterization data for new compounds can be found
with this article in the online version at doi:10.1016/
j.tetlet.2005.05.094.
References and notes
1. The first synthesis of pentamethylcyclopentadiene: de
Vries, L. J. Org. Chem. 1960, 25, 1838.
10. For similar protective methods, see: (a) Comins, D. L.
Synlett 1992, 615–625; (b) Ohta, S.; Hayakawa, S.;
Nishimura, K.; Okamoto, M. Tetrahedron Lett. 1984,
25, 3251–3254; (c) Nakamura, H.; Aoyagi, K.; Yama-
moto, Y. J. Org. Chem. 1997, 62, 780–781. Also see Ref. 4,
348–350, 361–363.
2. Initial examples of the synthesis of Cp*–metal complexes:
(a) King, R. B.; Bisnette, M. B. J. Organomet. Chem. 1967,
8, 287–297; (b) Ro¨hl, H.; Lange, E.; Go¨ssl, T.; Roth, G.
Angew. Chem., Int. Ed. Engl. 1962, 1, 117.