Direct preparation of copper organometallics bearing an aldehyde function via an iodine-copper exchange

Article abstract of DOI:10.1039/b604259g

The iodine-copper exchange reaction allows the direct preparation of various aryl, heteroaryl and alkenyl cuprates bearing a formyl group, thus allowing a direct synthesis of polyfunctional aldehydes without the need of protecting groups or an additional oxidation step. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b604259g

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Direct preparation of copper organometallics bearing an aldehyde
function via an iodine–copper exchange{
Xiaoyin Yang and Paul Knochel*
Received (in Cambridge, UK) 23rd March 2006, Accepted 7th April 2006
First published as an Advance Article on the web 3rd May 2006
DOI: 10.1039/b604259g
The iodine–copper exchange reaction allows the direct prepara-
tion of various aryl, heteroaryl and alkenyl cuprates bearing a
formyl group, thus allowing a direct synthesis of polyfunctional
aldehydes without the need of protecting groups or an
additional oxidation step.
Polyfunctionalized organometallics are versatile intermediates in
modern organic chemistry, since they allow the formation of
multifunctional products.1 One of the best preparation methods of
these organometallic reagents is the halogen–metal exchange
reaction.1e,2 The halogen–magnesium3 and halogen–copper4
exchanges have recently been extensively investigated. They allow
Scheme 1
the convenient preparation of polyfunctional aryl, heteroaryl and
alkenyl organometallic reagents that bear various functional
groups. The formyl group is present in numerous compounds,
but has been regarded as being incompatible with most
organometallic reagents.5 Only scarce examples of formyl-
substituted aryl organometallic compounds have been reported.6
In most cases, tedious protection and deprotection steps or an
additional oxidation step are required to introduce this sensitive
function in a target molecule.7 Herein, we wish to report that the
iodine–copper exchange reaction allows the direct preparation of
polyfunctional aryl, heteroaryl and alkenyl copper reagents
bearing an aldehyde group. Subsequent reactions of these
formyl-substituted copper reagents with various electrophiles
provide highly functionalized aldehydes in good yields. In a
preliminary experiment, we have treated 4-acetoxy-3-iodo-5-
methoxybenzaldehyde (1a) with lithium dineophylcuprate
[(PhMe2CCH2)2CuLi:(Nphyl)2CuLi (2)] in a 5:1 mixture of THF
and diethyl ether at 278 uC. Within 2 h, a complete iodine–copper
exchange reaction was observed, as indicated by GC-analysis of a
reaction aliquot. The resulting arylcopper reagent 3a reacted
smoothly with allyl bromide and cyclohexanecarbonyl chloride
between 278 uC and rt giving the expected aldehydes 4a and 4b in
84% and 73% yield (Scheme 1, entries 1 and 2 of Table 1). The use
of more reactive and less sterically hindered lithium dineopentyl-
cuprate [(Me3CCH2)2CuLi] led to a complex reaction mixture and
the use of the lithium cuprate (2) is mandatory for the success of
the exchange.
reaction with (Nphyl)2CuLi (2) giving the desired aldehydes 4c
and 4d in 80–94% yield after reactions with allyl bromide and
benzoyl chloride (entries 3 and 4). Remarkably, this iodine–copper
exchange reaction could also be extended to heteroaryl substrates.
Thus, 5-iodo-2-thiophenecarbaldehyde (1c) reacted readily with
(Nphyl)2CuLi (2) at 278 uC within 10 min, furnishing the copper
reagent 3c, which reacted with electrophiles, such as ethyl
(2-bromomethyl)acrylate, benzoyl chloride or 2-thiophene carbo-
nyl chloride, affording the highly functionalized 4e–g in 72–85%
yield (entries 5, 6 and 7). In a similar way, the heterocyclic iodo-
aldehydes 1d–e could be easily converted into the corresponding
copper reagents 3d–e under our standard reaction conditions.
Subsequent reactions with various electrophiles led to highly
functionalized aldehydes 4h–i in 61–79% yield (entries 8 and 9).
The presence of an adjacent heteroatom (O, N or S) decreases the
reactivity of these copper heterocycles 1c–e sufficiently so that no
addition to the aldehyde occurred under the exchange reaction.
Furthermore, this exchange could be applied to indoles bearing a
formyl group at the 2 or 3 position. Thus, N-protected
3-iodoindole-2-carbaldehyde (1f) underwent a smooth I–Cu-
exchange reaction with (Nphyl)2CuLi (2) at 278 uC within
30 min, leading to the cuprate 3f. The subsequent treatment with
allyl bromide furnished 3-allylated indole 4j in 83% yield (entry 10).
Interestingly, even with the sterically hindered indole derivative 1g,
the exchange reaction proceeded smoothly, yielding the function-
alized cuprate 3g, which was readily allylated providing the
aldehyde 4k in 93% yield (entry 11). Finally, the functionalized
pyridine 1h reacted readily with (Nphyl)2CuLi (2, 1.2 equiv.) in a
5:1 mixture of THF and ether from 278 uC to 260 uC, leading to
the corresponding cuprate 3h, which was quenched with ethyl
(2-bromomethyl)acrylate or benzoyl chloride forming the trisub-
stituted functionalized pyridines 4l and 4m in 82% and 63% yields
(entries 12 and 13).
Interestingly, in the case of 3,5-diiodo-2-tosyloxybenzaldehyde
(1b), the ortho-iodine underwent a selective I–Cu-exchange
Department Chemie, Ludwig-Maximilians-Universita¨t Mu¨nchen,
Butenandtstr. 5-13, Haus F, 81377 Mu¨nchen, Germany.
E-mail: Paul.Knochel@cup.uni-muenchen.de;
Fax: (+49)-89-2180-77680; Tel: (+49)-89-2180-77681
{ Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b604259g
2486 | Chem. Commun., 2006, 2486–2488
This journal is ß The Royal Society of Chemistry 2006

View Article Online
Table 1 Aldehydes of type 4 obtained by the reaction of formyl-
substituted aryl and heteroaryl copper reagents 3 with electrophiles
Yield
Electrophile Product of type 4 (%)a
Entry Copper reagent
1
84
Scheme 2
2
3
4
3a
c-HexCOCl
73e
94
3b
PhCOCl
80
Scheme 3
The resulting highly functionalized aldehydes of type 4 can be
readily converted to polyfunctional heterocycles of potential
pharmaceutical interest. The reaction of the dicarbonylated
pyridine 4m with hydrazine monohydrate in ethanol (reflux,
15 min) provided pyridopyridazine 5 in 95% yield (Scheme 2).8
Furthermore, this exchange reaction also allows the function-
alization of b-iodo-a,b-unsaturated aldehydes. The reaction of
(Z)-3-iodo-2-heptenal (6) with (Nphyl)2CuLi (2) in THF at
2100 uC (5 min) stereoselectively furnished the alkenyl cuprate
7. The Z configuration of the double bond (stabilized by
chelation)9 as well as the presence of the sterically hindered butyl
group disfavored an addition–elimination reaction and favored the
I–Cu-exchange reaction.10 Treatment of the cuprated unsaturated
aldehyde 7 with allyl bromide or ethyl (2-bromomethyl)acrylate
furnished the trisubstituted a,b-unsaturated aldehydes 8a and 8b in
81% and 73% yields (Scheme 3).
5
6
85
80
3c
3c
PhCOCl
7
72
8
9
PhCOCl
61g
79
In summary, we have shown that the iodine–copper exchange
reaction allows the direct preparation of various new aryl,
heteroaryl and alkenyl cuprates bearing an aldehyde group, thus
expanding the applications of functionalized copper organome-
tallic species in organic synthesis.11 Further extensions of this
method are currently underway in our laboratory.
10
83
11
12
93
82
63
Notes and references
1 (a) N. Krause, Modern Organocopper Chemistry, Wiley-VCH,
Weinheim, 2002; (b) M. d’Augustin, L. Palais and A. Alexakis,
Angew. Chem., Int. Ed., 2005, 44, 1376; (c) B. L. Feringa, R. Badorrey,
D. Pen˜a, S. R. Harutyunyan and A. J. Minnaard, Proc. Natl. Acad. Sci.
U. S. A., 2004, 101, 5834; (d) R. Naasz, L. A. Arnold, M. Pineschi,
E. Keller and B. L. Feringa, J. Am. Chem. Soc., 1999, 121, 1104; (e)
P. Knochel, Handbook of Functionalized Organometallics, Wiley-VCH,
Weinheim, 2005; (f) I. Marek and J.-F. Normant, Chem. Rev., 1996, 96,
3241.
13
3h
PhCOCl
2 (a) W. F. Bailey and J. J. Patricia, J. Organomet. Chem., 1988, 352, 1; (b)
W. F. Bailey and E. R. Punzalan, J. Org. Chem., 1990, 55, 5404; (c) W.
F. Bailey, J. D. Brubaker and K. P. Jordan, J. Organomet. Chem., 2003,
681, 210; (d) E. Negishi, D. R. Swanson and C. J. Rousset, J. Org.
Chem., 1990, 55, 5406; (e) G. Boche, M. Schimeczek, J. Cioslowski and
P. Piskorz, Eur. J. Org. Chem., 1998, 1851; (f) H. J. Reich, M. J. Bevan,
a
Isolated yields of analytically pure aldehydes.
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 2486–2488 | 2487

View Article Online
B. O. Gudmundsson and C. L. Puckett, Angew. Chem., 2002, 114, 3586,
Angew. Chem., Int. Ed., 2002, 41, 3436; (g) C. E. Tucker, T. N. Majid
and P. Knochel, J. Am. Chem. Soc., 1992, 114, 3983; (h) R. W.
Hoffmann, P. G. Nell, R. Leo and K. Harms, Chem.–Eur. J., 2000, 6,
3359; (i) R. W. Hoffmann, B. Ho¨lzer, O. Knopff and K. Harms, Angew.
Chem., 2000, 112, 3206, Angew. Chem., Int. Ed., 2000, 39, 3072.
3 (a) L. Boymond, M. Rottla¨nder, G. Cahiez and P. Knochel, Angew.
Chem., 1998, 110, 1801, Angew. Chem., Int. Ed., 1998, 37, 1701; (b)
A. Boudier, L. O. Bromm, M. Lotz and P. Knochel, Angew. Chem.,
2000, 112, 4584, Angew. Chem., Int. Ed., 2000, 39, 4414; (c) A. E. Jensen,
W. Dohle, I. Sapountzis, D. M. Lindsay, V. A. Vu and P. Knochel,
Synthesis, 2002, 565; (d) P. Knochel, W. Dohle, N. Gommermann,
F. F. Kneisel, F. Kopp, T. Korn, I. Sapountzis and V. A. Vu, Angew.
Chem., 2003, 115, 4438, Angew. Chem., Int. Ed., 2003, 42, 4302.
4 (a) E. J. Corey and G. H. Posner, J. Am. Chem. Soc., 1968, 90, 5615; (b)
Y. Kondo, T. Matsudaira, J. Sato, N. Muraka and T. Sakamoto,
Angew. Chem., 1996, 108, 818, Angew. Chem., Int. Ed. Engl., 1996, 35,
736; (c) C. Piazza and P. Knochel, Angew. Chem., Int. Ed., 2002, 41,
3263; (d) X. Yang, T. Rotter, C. Piazza and P. Knochel, Org. Lett.,
2003, 5, 1229; (e) X. Yang and P. Knochel, Synlett, 2004, 81; (f) X. Yang,
A. Althammer and P. Knochel, Org. Lett., 2004, 6, 1665; (g) X. Yang
and P. Knochel, Synlett, 2004, 2303.
7 (a) A. T. Khan, E. Mondal, S. Ghosh and S. Islam, Eur. J. Org. Chem.,
2004, 2002; (b) R. Bernini, A. Coratti, G. Provenzano, G. Fabrizi and
D. Tofani, Tetrahedron, 2005, 61, 1821; (c) M. P. Groziak and L. Wei,
J. Org. Chem., 1991, 56, 4296; (d) M. P. Groziak and L. Wei, J. Org.
Chem., 1992, 57, 3776; (e) D. L. Comins and M. O. Killpack, J. Org.
Chem., 1990, 55, 69; (f) D. L. Comins and M. O. Killpack,
J. Org. Chem., 1987, 52, 104.
8 M. J. Haddadin, B. J. Agha and R. F. Tabri, J. Org. Chem., 1979, 44,
494.
9 V. Snieckus, Chem. Rev., 1990, 90, 879.
10 I. Sapountzis, W. Dohle and P. Knochel, Chem. Commun., 2001,
2068.
11 Preparation of 3-allyl-5-iodo-2-tosyloxybenzaldehyde (4c): a dry and
argon flushed 25 mL flask, equipped with a magnetic stirring bar and a
septum, was charged with CuCN (108 mg, 1.2 mmol) and dry THF
(4 mL). A solution of neophyllithium (1.3 M in Et2O, 1.8 mL, 2.4 mmol)
was added at 278 uC. After stirring at rt for 10 min, the reaction
mixture was cooled to 278 uC and transferred by cannula into a mixture
of 3,5-diiodo-2-tosyloxybenzaldehyde (1b, 528 mg, 1.0 mmol) in dry
THF (5 mL) at 278 uC. The resulting mixture was stirred at 278 uC for
20 min. Allyl bromide (360 mg, 3.0 mmol) was added and the reaction
mixture was stirred at rt for 30 min. The reaction mixture was quenched
with saturated aqueous NH4Cl solution (5 mL) and poured into water
(15 mL). The aqueous phase was extracted with CH2Cl2 (3 6 20 mL).
The organic fractions were washed with brine (30 mL), dried over
Na2SO4 and concentrated in vacuo. The residue was purified by flash-
chromatography to give the desired product 4c (415 mg, 94% yield) as a
colorless oil.
5 (a) J. Otera, Modern Carbonyl Chemistry, Wiley-VCH, Weinheim, 2000;
(b) J. R. Hanson, Functional Group Chemistry, RSC Publishing, UK,
2001.
6 (a) F. F. Kneisel, M. Dochnahl and P. Knochel, Angew. Chem., Int. Ed.,
2004, 43, 1017; (b) F. F. Kneisel, H. Leuser and P. Knochel, Synthesis,
2005, 2625.
2488 | Chem. Commun., 2006, 2486–2488
This journal is ß The Royal Society of Chemistry 2006