A simple one-pot organometallic formylation/trapping sequence using N-formylcarbazole

Article abstract of DOI:10.1055/s-2004-822896

Treatment of a range of sp³-, sp²- and sp-nucleophiles with N-formyl carbazole leads to the formation of the metastable anionic carbazole carbinols. In the presence of a second nucleophilic reagent such as phosphonoacetate or an organolithium, these collapse on warming to the aldehyde which is trapped in situ to afford the α,β-unsaturated esters or secondary carbinols respectively.

Full text of DOI:10.1055/s-2004-822896

1092
LETTER
A Simple One-pot Organometallic Formylation/Trapping Sequence Using
N-Formylcarbazole
A
Simple
One-pot
a
O
rganomet
r
a
llic
F
or
r
m
ylation
e
/Trapping
nSequence J. Dixon,* Amanda C. Lucas
University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
Fax +44(1223)336362; E-mail: djd26@cam.ac.uk
Received 30 January 2004
latter, the unpleasant odour associated with the skatole
Abstract: Treatment of a range of sp3-, sp2- and sp-nucleophiles
with N-formyl carbazole leads to the formation of the metastable
anionic carbazole carbinols. In the presence of a second nucleo-
philic reagent such as phosphonoacetate or an organolithium, these
starting material focused our attention on other formyla-
tion sources. N-Formylcarbazole 2 was subsequently
identified as the reagent of choice. The parent heterocycle
collapse on warming to the aldehyde which is trapped in situ to af- is cheap and the synthesis can be efficiently carried out on
ford the a,b-unsaturated esters or secondary carbinols respectively.
a large scale by simply boiling carbazole 1 in formic acid
for 8 hours and the product is isolated by crystallization
(Scheme 2).9
Key words: carbinols, enynes, formylation, heterocycles, N-
formylcarbazole
O
H
H
N
Methods for the formylation of organometallic reagents1,2
have received much attention over the years due to the ob-
vious synthetic utility of the one carbon homologation
procedure and the wealth of reactions possible with the
aldehyde product.3,4 For sp3-, sp2- or sp-carbanions, the
formylating agent is invariably based around an N-
formylated amine, which is not only reactive towards the
organometallic, but the resulting anionic carbinol is stable
until dilute acidic work-up and only then is the aldehyde
released. Reports by our group5 and others6 have revealed
that while N-carbinols of pyrrole are stable in their neutral
state, they may be collapsed back to the parent carbonyl
compound under basic conditions. This metastability
lends itself to the possibility of a one-pot multicomponent
formyl transfer/aldehyde trapping procedure7,8 using N-
formyl heterocycles as the reagent (Scheme 1) and herein
we wish to report our findings.
N
HCOOH, ∆
88%
2
1
Scheme 2
With multigram quantities of N-formylcarbazole 2 in
hand, the sequential formylation/aldehyde trapping se-
quence was investigated. The addition of a range of
nucleophiles to 2 was carried out at –78 °C, followed by
the addition of Wadsworth–Horner–Emmons reagent.
The resulting a,b-unsaturated esters were obtained in rea-
sonable to good yields over the two steps (Scheme 3,
Table 1, General Procedure A).
O
i) 2, THF
R1M
R1
OR2
O
O
P
ii)
R2O
3a–g
OM
O
OEt
OEt
O
R1-M
N
R1
N
H
Scheme 3
R1
H
Table 1 One-pot Organometallic Formylation and Wadsworth–
Horner–Emmons Reaction (General Procedure A)
R2-M
Entry
R1M
R2
Product
3a
Yield (%) E:Z
H3O+
OM
1
2
3
4
5
6
7
n-BuLi
n-BuLi
n-BuLi
s-BuLi
Et
82
71
79
50
46
45
68
25:1
Product
R1
R2
t-Bu
Bn
Et
3b
15:1
24:1
Scheme 1
3c
Initially, N-formylpyrrole and N-formyl-3-methylindole
were considered as potential candidates. However in the
former case, synthesis was a major set-back and in the
3d
14:1
i-PrMgCl Bn
i-PrMgBr Bn
3e
>50:1
29:1
3f
SYNLETT 2004, No. 6, pp 1092–1094
0
6.
0
5.
2
0
0
4
PhLi
Bn
3g
>50:1
Advanced online publication: 25.03.2004
DOI: 10.1055/s-2004-822896; Art ID: D02104ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
A Simple One-pot Organometallic Formylation/Trapping Sequence
1093
It was pleasing that both aliphatic and aromatic organo- However the overwhelming advantage of the N-formyl-
metallic nucleophiles could be used in these reactions (en- carbazole approach lay in the metastability of the interme-
tries 1–6 vs. entry 7) and that moderate to high yields of diate metal alkoxide, such that with appropriate control, it
the product could be obtained, irrespective of the nature was envisaged possible to give the mixed product in high
of the Wadsworth–Horner–Emmons reagent used (entries selectivity, in contrast to the statistical 1:2:1 mixture
1–3).
anticipated with traditional formylating agents.
More specifically, of the a,b-unsaturated esters, good Upon optimization, the protocol led to formation of the
yields were obtained when primary alkyl lithium and phe- desired mixed dialkynes in greater than 10:1 selectivity
nyl lithium reagents were used (entries 1–3 and 7). With over the undesired symmetrical dialkynes and the
secondary alkyl lithiums and secondary Grignard re- products were isolated in good yields (Table 3, entries 4
agents, the yields were somewhat lower, but still accept- and 5).
able (entries 4–6). The diminished yields presumably
To further demonstrate the scope of this method, sp3- and
arose from competing proton transfer reactions.
sp2- nucleophiles were also used in unsymmetrical prod-
To circumvent this problem and enhance the scope of the uct formation (entries 6 and 7). The consistently good
reaction, alkynyl lithium reagents were explored in the se- yields obtained suggest the method should be general for
quential formylation/WHE reaction (Scheme 4, Table 2). a wide range of organometallic reagents (Scheme 5).
OH
R2
i) 2, THF
O
i) n-BuLi
ii) 2, THF
R1Li
ii) R2Li
R1
OR2
R1
O
ii)
O
P
R1
5a–g
R2O
4a–d
OEt
OEt
Scheme 5
Scheme 4
Table 3 Aldehyde Trapping with a Second Organolithium (General
Procedure C)
Table 2 Enyne Synthesis (General Procedure B)
Entry R1
R2
Prod- Yield
R1
Et
Et
Product Yield
(%)
E:Z
uct
(%)
Entry Substrate
Li
1
2
5a
67
Li
1
4a
4b
4c
90
100
89
30:1
3
5b
5c
5d
5e
74
70
67
71
Li
Li
O
O
O
O
2
>50:1
>50:1
7
3
4
5
3
Et
Li
Li
4
Bn
4d
65
30:1
O
O
Li
Li
Li
O
O
O
O
Li
As anticipated, enyne formation10,11 proceeded in good to
excellent yield for both simple (entries 1, 2) and function-
alized (entries 3, 4) alkynes (General Procedure B).
6
7
5f
81
70
Li
Li
Li
While these products 4a–d allow scope for further func-
tionalization, we were keen to investigate other nucleo-
philic addition reactions to the in situ generated aldehyde.
5g
Li
To test that the addition of a second organolithium to the
crude aldehyde could proceed smoothly, three alkyne
dimerization reactions were carried out, and pleasingly,
the products were isolated in good to excellent yields
(Table 3, entries 1–3). The dialkyne motifs are frequently
found in natural product compounds and synthetic inter-
mediates thereof.12,13
In summary, we have demonstrated the utility of readily
prepared N-formylcarbazole as a reagent for a novel se-
quential formylation and aldehyde trapping procedure.
This has been illustrated in the one-pot synthesis of a,b-
unsaturated esters as well as symmetrical and unsymmet-
rical carbinols by sequential addition of a first, then a sec-
ond carbon centered nucleophile. Further work directed
There is no doubt that this procedure would work equally
well using ethyl formate as the one carbon electrophile.
Synlett 2004, No. 6, 1092–1094 © Thieme Stuttgart · New York

1094
D. J. Dixon, A. C. Lucas
LETTER
towards extending the scope of this procedure regarding
the range of secondary nucleophiles used to trap the inter-
mediate aldehyde is underway.
Acknowledgment
We wish to thank the EPSRC (to ACL) and GlaxoSmithKline (to
ACL) for funding, the EPSRC Swansea Mass Spectrometry Service
and Prof. S. V. Ley for continued support. We would like to thank
Dr. Jeremy C. Prodger of GSK for useful discussions.
Synthesis of N-Formylcarbazole (2)
A mixture of carbazole (50.0g, 0.30 mol) and formic acid (375 mL)
was heated under reflux overnight. Formic acid was removed by
distillation. The product was recrystallized (EtOAc) to give the title
compound as white crystals (44.1 g, 88%). The spectral data was in
agreement with literature values.14
References
(1) (a) For a comprehensive review, see: Olah, G. A.;
Ohannesian, L.; Arvanaghi, M. Chem. Rev. 1987, 87, 671;
and references cited therein. (b) Amaratunga, W.; Fréchet,
J. M. J. Tetrahedron Lett. 1983, 24, 1143. (c) Shirley, D. A.
Org. React. 1954, 8, 28.
General Procedure A
To a solution of N-formylcarbazole (2 mmol) in THF (8 mL) at
–78 °C was added the organometallic reagent (2.2 mmol). The reac-
tion mixture was stirred for 1 h at –78 °C, then warmed to –10 °C
before the addition of benzyldiethylphosphonoacetate (2.5 mmol).
The reaction mixture was allowed to warm to r.t. overnight then
washed with distilled H2O and brine. The crude reaction mixture
was concentrated in vacuo and purified by flash column chromato-
graphy (40–60 petroleum ether and Et2O). The products were
characterized and where relevant, confirmed by comparison with
the literature.
(2) For more recent reports of formylation of organolithiums,
see: (a) Lipshutz, B. H.; Pfeiffer, S. S. Tetrahedron Lett.
1999, 40, 7889. (b) Journet, M.; Cai, D.; DiMichele, L. M.;
Larsen, R. D. Tetrahedron Lett. 1998, 39, 6427.
(3) For a one-pot alcohol oxidation/aldehyde trapping
procedure, see: Bagley, M. C.; Hughes, D. D.; Sabo, H. M.;
Taylor, P. H.; Xiong, X. Synlett 2003, 1443.
(4) Taylor has reported a number of such processes, for example
see: (a) Foot, J. S.; Kanno, H.; Giblin, G. M. P.; Taylor, R. J.
K. Synthesis 2003, 1055. (b) Blackburn, L.; Wei, X.; Taylor,
R. J. K. Chem. Commun. 1999, 1337.
General Procedure B
(5) Dixon, D. J.; Luckhurst, C. A.; Scott, M. S. Synlett 2003,
2317.
(6) (a) Brandänge, S.; Holmgren, E.; Leijonmarck, H.;
Rodriguez, B. Acta Chem. Scand. 1995, 49, 922. (b) Evans,
D. A.; Borg, G.; Scheidt, K. A. Angew. Chem. Int. Ed. 2002,
41, 3188.
(7) For an example of a formylation-aldol condensation system
using DMF, see: Würthner, F. Synthesis 1999, 2103.
(8) For a comparable procedure, see: Turos, E.; Boy, K.; Ren, X.
J. Org. Chem. 1992, 57, 6667.
(9) Adapted from an earlier procedure: Chakrabarty, M.;
Khasnobis, S.; Harigaya, Y.; Konda, Y. Synth. Commun.
2000, 30, 187.
To a solution of the alkyne (2.2 mmol) in THF (5 mL) at –78 °C,
was added n-butyllithium (2.2 mmol) and the solution stirred for 10
min before being added to a solution of N-formylcarbazole (2
mmol) in THF (3 mL) at –78 °C. The reaction mixture was stirred
for 1 h at –78 °C then warmed to –10 °C before the addition of ben-
zyldiethylphophonoacetate (2.5 mmol). The reaction mixture was
allowed to warm to r.t. overnight, and Et2O and H2O were added.
The aqueous layer was extracted with Et2O and the combined or-
ganic layers were washed with brine, concentrated in vacuo and pu-
rified by flash column chromatography, (40–60 petroleum ether and
Et2O). The products were characterized and where relevant, com-
pared with the literature.
(10) Barrett, A. G. M.; Hamprecht, D.; Ohkubo, M. J. J. Org.
Chem. 1997, 62, 9376.
(11) Takeuchi, R.; Tanabe, K.; Tanaka, S. J. Org. Chem. 2000,
65, 1559.
(12) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.;
Prinsep, M. R. Nat. Prod. Rep. 2003, 20, 1.
(13) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123,
9687.
General Procedure C
To a solution of N-formylcarbazole (2 mmol) in THF (3 mL) at
–78 °C was added a –78 °C solution of the first organolithium
(2 mmol) in THF (3 mL). The reaction mixture was stirred for 1 h
before the addition of a –78 °C solution of the second organolithium
(2 mmol) in THF (3 mL). The reaction mixture was warmed to r.t.
over 3.5 h, then quenched by the addition of H2O. The reaction mix-
ture was diluted with 40–60 petroleum ether, then filtered through
cotton wool to remove most of the carbazole, then purified by flash
column chromatography (40–60 petroleum ether and Et2O). The
products were characterized and where relevant, compared with the
literature.
(14) Flo, C.; Pindur, U. Liebigs Ann. Chem. 1987, 509.
Synlett 2004, No. 6, 1092–1094 © Thieme Stuttgart · New York