New family of cyclopropanating reagents: Synthesis, reactivity, and stability studies of iodomethylzinc phenoxides

Article abstract of DOI:10.1002/1521-3773(20001215)39:24<4539::AID-ANIE4539>3.0.CO;2-9

A valuable alternative to the traditional Simmons-Smith reagents is offered by the title compounds, as a result of their ease of preparation and high reactivities towards unfunctionalized olefins (see scheme).

Full text of DOI:10.1002/1521-3773(20001215)39:24<4539::AID-ANIE4539>3.0.CO;2-9

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signal at m/z 466 =see Supporting Information; Figure S3).
[7] L. M. Ellerby, D. E. Cabelli, J. A. Graden, J. S. Valentine, J. Am.
Chem. Soc. 1996, 118, 6556 ± 6561.
The observed mass and isotope patterns are consistent with
[
[
8] D. T. Sawyer, J. S. Valentine, Acc. Chem. Res. 1981, 14, 393 ± 400.
9] H. A. Azab, L. Banci, M. Borsari, C. Luchinat, M. Sola, M. S. Viezzoli,
Inorg. Chem. 1992, 31, 4649 ± 4655.
‡
withthe ion [Zn=QH){MeIm=Py) }] , which is the protonated
2
.
À
‡
form of the reduced species of [Zn=Q ){MeIm=Py) }] .
2
II
In conclusion, the Zn ion in the SOD model complex has
[10] H. Ohtsu, Y. Shimazaki, A. Odani, O. Yamauchi, S. Itoh, S. Fukuzumi,
J. Am. Chem. Soc. 2000, 122, 5733 ± 5741.
been shown to play the essential role in facilitating the
.
À
.À
II
[11] a) M. Sato, S. Nagae, M. Uehara, J. Nakaya, J. Chem. Soc. Chem.
Commun. 1984, 1661 ± 1663; b) Q. Lu, Q. H. Luo, A. B. Dai, Z. Y.
Zhou, G. Z. Hu, J. Chem. Soc. Chem. Commun. 1990, 1429 ± 1431;
c) M. Zongwan, C. Dong, T. Wenxia, Y. Kaibei, L. Li, Polyhedron
1992, 11, 191 ± 196; d) J.-L. Pierre, P. Chautemps, S. Refaif, C. Beguin,
A. E. Marzouki, G. Serratrice, E. Saint-Aman, P. Rey, J. Am. Chem.
Soc. 1995, 117, 1965 ± 1973; e) Z.-W. Mao, M.-Q. Chen, X.-S. Tan, J.
Liu, W.-X. Tang, Inorg. Chem. 1995, 34, 2889 ± 2893.
12] S. Fukuzumi, S. Koumitsu, K. Hironaka, T. Tanaka, J. Am. Chem. Soc.
1987, 109, 305 ± 316.
13] R. H. Schuler, G. N. R. Tripathi, M. F. Prebenda, D. M. Chaipman, J.
Phys. Chem. 1983, 87, 5357 ± 5361.
reduction of Q by coordination of Q to the Zn ion. The
.
À
II
oxidation of Q is also facilitated by the Zn ion, since the
II
reduction potential of the Cu center in the imidazolate-
bridged Cu ± Zn heterodinuclear complex 1 is shifted to a
more positive value =0.21 V) relative to that without a Zn
II
II
II
[
10]
II
ion. Thus, the Zn ion can facilitate boththe oxidation and
.
À
reduction of Q . Essentially the same mechanism may also
[
[
[
.
À
be applied to the disproportionation of O2 catalyzed by
Zn,Cu-SOD.
14] a) K. Palmo, J.-O. Pietila, B. Mannfors, A. Karonen, F. Stenman, J.
Mol. Spectrosc. 1983, 100, 368 ± 376; b) D. M. Chipman, M. F. Preb-
enda, J. Phys. Chem. 1986, 90, 5557 ± 5560.
Experimental Section
[
15] G. N. R. Tripathi, J. Am. Chem. Soc. 1998, 120, 5134 ± 5135.
To a deaerated solution =25 mL) of p-benzoquinone =8.10 mg) in EtCN and
[16] S. Fukuzumi, T. Okamoto, J. Am. Chem. Soc. 1994, 115, 11600 ± 11601.
1
hydroquinone =8.25 mg) was added two equivalents of 1m Bu
4
NOH ´
[17] [Zn{MeIm=Py)
2
}=CH
3
CN)]=ClO
4
)
2
:
3
H NMR =400 MHz, CD CN,
MeOH solution =72 mL) to make the stock solution of p-benzosemiquinone
258C, TMS): d ˆ 3.82 =s, 3H; CH
3
), 4.00 =s, 2H; NCH
Py), 7.19 =s, 1H; Im), 7.68 =d, J=H,H) ˆ
2
Im), 4.26 =d,
.
À
À3
3
3
radical anion Q =6.0 Â 10 m). The reactions of imidazolate-bridged
J=H,H) ˆ 4.8 Hz, 4H; NCH
2
II
II
II
II
4
Cu ± Zn heterodinuclear and Cu ± Cu homodinuclear SOD model
complexes and semiquinone radical anion were performed in a UV/Vis cell
7.6 Hz, 2H; Py), 7.76 =m, 2H; Py), 8.09 =s, 1H; Im), 8.21 =td, J=H,H) ˆ
3
1.6, J=H,H) ˆ 8.0 Hz, 2H; Py), 8.81 =m, 2H; Py); elemental analysis
=
=
path length 1 cm) which was held in a Unisoku temperature-controlled
calcd for C19
H
23
N
6
Zn
1
Cl
2
O
8.5 =%): C 37.55, H 3.81, N 13.83; found: C
‡
Æ0.58C) cell holder designed for low-temperature experiments. After the
37.43, H 3.49, N 13.95; ESI MS data: m/z: 456 [M À ClO
4
] . For the
À4
deaerated solution of the SOD model complexes =0.1 Â 10 m) in the cell
details of the synthetic procedure for the ligand MeIm=Py)
reference [10].
2
, see
had been kept at the desired temperature for several minutes, semiquinone
I
radical anion was added by syringe. Formation of the Cu ± Q complexes
[18] In the case of 1, the appearance of a new absorption band at 570 nm
I
was followed by monitoring the absorption change at 585 nm. The rate
was obscured by the absorption band at 590 nm due to the Cu ± Q
complex.
.
À
constant
k
obs for the stoichiometric disproportionation of
Q
was
determined by monitoring the decrease in the absorption band due to
[19] S. Fukuzumi, Y. Ono, T. Keii, Bull. Chem. Soc. Jpn. 1973, 46, 3353 ±
.
À
Q
=lmax ˆ 422 nm).
3355.
Frozen-solution ESR spectra were recorded on a JEOL JES-RE1X X-band
spectrometer equipped witha standard low-temperature apparatus. All
spectra were recorded at 77 K in quartz tubes with4 mm inner diameters.
II
The g values were calibrated witha Mn marker as a reference.
Resonance Raman spectra were excited at 632.8 nm withan He ± Ne laser
and detected witha JASCO NR-1800 triple polychromator equipped witha
liquid-nitrogen-cooled Princeton Instruments CCD detector. Raman
measurements were carried out witha spinning cell, and t he laser power
was adjusted to 50 mW at the sample point. Raman shifts were calibrated
New Family of Cyclopropanating Reagents:
Synthesis, Reactivity, and Stability Studies of
Iodomethylzinc Phenoxides**
Andr e B. Charette,* S e bastien Francoeur,
Jonathan Martel, and Nicole Wilb
with acetonitrile; the accuracy of the peak positions of the Raman bands
À1
was Æ1cm
.
ESI mass spectra were obtained withan API 150 triple quadrupole mass
spectrometer =PE-Sciex) in positive-ion detection mode, equipped withan
ion-spray interface. The sprayer was held at a potential of 5.0 kV, and
The cyclopropanation of olefins is a very useful process in
synthetic organic chemistry. Cyclopropane moieties are found
compressed N
2
was employed to assist liquid nebulization. The positive-ion
in many natural[ and unnatural products possessing inter-
1]
[2]
ESI mass spectra were measured in the range m/z 100 ± 1000.
[3]
esting biological activities. These units are also very useful
synthons for further synthetic transformations.[
4]
Received: August 22, 2000 [Z15682]
Amongst the different methods of cyclopropanation, the
Simmons ± Smithreaction [ has stimulated a considerable
5]
[
1] a) I. Fridovich, J. Biol. Chem. 1989, 264, 7761 ± 7764; b) I. Fridovich,
[
*] Prof. A. B. Charette, S. Francoeur, J. Martel, N. Wilb
D e partement de Chimie
Universit e de Montr e al
Annu. Rev. Biochem. 1995, 64, 97 ± 112.
[
[
2] I. Bertini, L. Banci, M. Piccioli, Coord. Chem. Rev. 1990, 100, 67 ± 103.
3] J. A. Tainer, E. D. Getzoff, K. M. Beem, J. S. Richardson, D. C.
Richardson, J. Mol. Biol. 1982, 160, 181 ± 217.
P.O. Box 6128, Station Downtown, Montr e al =Canada)
Fax : =‡1)514-343-5900
[
4] J. A. Tainer, E. D. Getzoff, J. S. Richardson, D. C. Richardson, Nature
E-mail: andre.charette@umontreal.ca
1
983, 306, 284 ± 287.
[
5] P. J. Hart, M. M. Balbirnie, N. L. Ogihara, A. M. Nersissian, M. S.
[**] This work was supported by the E.W.R. Steacie Fund, the National
Science and Engineering ResearchCouncil =NSERC) of Canada,
Merck Frosst Canada, Boehringer Ingelheim =Canada), F.C.A.R.
=Qu e bec), and the Universit e de Montr e al. J.M. and S.F. are grateful
to NSERC and F.C.A.R. respectively for postgraduate fellowships.
Weiss, J. S. Valentine, D. A. Eisenberg, Biochemistry 1999, 38, 2167 ±
2
178.
[
6] E. M. Fielden, P. B. Roberts, R. C. Bray, D. J. Lowe, G. N. Mautner, G.
Rotilio, L. Calabrese, Biochem. J. 1974, 139, 49 ± 60.
Angew. Chem. Int. Ed. 2000, 39, No. 24
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amount of interest within the chemical community.[6] Al-
though the initial method for the preparation of zinc
carbenoids witha zinc/copper couple was cumbersome,
several synthetically more accessible and reproducible meth-
ods quickly followed.[ Notable amongst these is the protocol
of Furukawa et al. which prepares a zinc carbenoid from
7]
[8]
Et Zn and CH I . This landmark observation allowed for
2
2 2
the reaction to take place in noncomplexing solvents, such as
dichloromethane or 1,2-dichloroethane,[9] which greatly im-
Scheme 2. Phenolic precursors for the cyclopropanating reagents.
proved the reactivity of zinc carbenoids for the cyclopropa-
nation of olefins.
2
Table 1. Reactivity of ArOZnCH I witharyl-substituted alkenes.
Despite the fact that zinc carbenoids have been studied
quite extensively, very little work has been done to modify the
nature of the R group of the zinc reagent ªRZnCH Xº and to
2
compare the reactivity of the new reagents to the classical
ones =when R ˆ I, Et, CH X). A few years ago, we demon-
2
strated that a new class of reagents ªROZnCH Iº =R ˆ alkyl
2
or allyl) are unreactive towards olefins in the absence of a
Lewis acid.[ Recently, Shi and co-workers reported that a
reagent prepared by mixing stoichiometric quantities of
Et Zn, trifluoroacetic acid, and CH I =which presumably
10]
[11]
[
a]
Conversion of alkenes [%]
Entry
Phenol
Equiv
14[b]
15
[c]
16
[d]
2
2 2
form ªRCOOZnCH Iº) displayed an increased reactivity
1
2
3
4
5
6
7
8
9
0
11
12
3
4
5
1
2
3
4
5
6
7
8
9
10
11
11
12
12
13
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.1
2.0
1.1
2.0
2.0
1.0
1.0
22
45
60
10
20
26
±
< 1
24
35
2
towards stilbene, a substrate that is often unreactive using
previously reported Simmons ± Smithprotocols. In t hi s com-
munication, we report that some reagents of general structure
±
44
> 95
> 95 =94)
> 95
57
87
66
> 95
89
> 95
> 95
> 95
85
> 95
> 95 =91)
95
30
27
18
85
73
95
79
89
50
47
> 95
> 95 =94)
88
45
20
15
91
95
94
94
> 95
58
50
93
ªArOZnCH Iº are very reactive species for the cyclopropa-
2
nation of unfunctionalized olefins. This synthetically useful
observation is a first step towards the development of an
enantioselective cyclopropanation method for unfunctional-
ized olefins.
1
The carbenoids ArOZnCH I can be easily prepared by two
2
1
1
1
different methods =Scheme 1). The phenol can be deproto-
nated upon treatment withEt Zn, and a subsequent metal ±
2
halogen exchange process with CH I leads to the formation
2
2
16
7
8
EtZnCH2I
Zn=CH
Zn=CH
1
1
2
I)
Cl)
2
86
> 95
2
2
> 95
[
[
a] Yields of isolated, analytically pure cyclopropanes are in parentheses.
1
2
3
1
2
3
1
2
b] 14: R ˆ CH
3
, R ˆ R ˆ H. [c] 15: R ˆ R ˆ R ˆ H. [d] 16: R ˆ R ˆ
H, R3 ˆ CH
2
-Ar.
The reactivity of the reagents is highly dependant upon the
position and nature of the substituents on the aromatic ring.
The first observation that can be made is the apparent need
for two ortho substituents to achieve high conversion into the
corresponding cyclopropyl derivative =entries 1 ± 3 versus
entries 5, 7, 11). This trend is a consequence of the self-
destruction of the reagent by an intramolecular electrophilic
aromatic substitution,[ which is otherwise prevented by
ortho substitution. Another striking feature of these reagents
is the beneficial effect of having a strong electron-withdraw-
ing group at the para position =entries 9 ± 11). Although a
Scheme 1. Two methods for the synthesis of ArOZnCH
corresponding phenol.
2
I from the
of the cyclopropanating reagent. Alternatively, one equiva-
lent of the phenol can be treated with one equivalent of
13]
[8]
Zn=CH I) . The first method is generally preferred since it
2
2
uses only one equivalent of diiodomethane and it does not
necessitate the prior formation of the less stable bis=iodome-
thyl)zinc.
clear trend between the pK of the phenol and the yield of
a
Several phenols =1 ± 13) possessing different substitution
patterns and acidities were screened =Scheme 2). To test the
reactivity of these reagents, three relatively unreactive olefins
were selected: a-methylstyrene =14), styrene =15), and indene
cyclopropanation has not been established, it is obvious that
having several electron-withdrawing groups is suitable. For
example, 2,4,6-trihalophenol-derived reagents 5 ± 7 =when
X ˆ F, Cl, and Br, respectively) produced very high yields of
cyclopropanes. This higher reactivity could result from an
increase in the electrophilicity of the zinc carbenoid and a
decrease in the nucleophilicity of the aromatic ring =thus
=
16). These unfunctionalized olefins were treated with the
zinc phenoxide reagents and the results are shown in
Table 1.[
12]
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preventing the rapid decomposition of the carbenoid). Of
special interest are the high reactivities of the carbenoids
prepared from phenols 11 and 12. Excellent conversions are
observed even when only 1.1 equivalents of the carbenoid are
used =entry 11 versus 12, and 13 versus 14). It is important to
note that the phenol by-product can be easily recovered in
nearly quantitative yield by flashchromatography or by acid-
base extraction after the reaction. The reagent derived from
In conclusion, the iodomethylzinc phenoxides offer a
valuable alternative to the traditional Simmons ± Smith re-
agents due to their ease of preparation, high reactivities
towards unfunctionalized olefins, and good stabilities. Further
work is currently underway to study the behavior of these
carbenoids in directed reactions and to develop an efficient
asymmetric cyclopropanation of unfunctionalized ole-
fins.[
14, 15]
2,4,6-trichlorophenol was more extensively studied since it
displayed a very high reactivity for the cyclopropanation
reaction and the precursor is cheap and readily available.
Direct comparison between the reactivity of traditional zinc
reagents and the 2,4,6-trichlorophenol-derived reagent indi-
cates that the latter is an equal or a better reagent for the
cyclopropanation of unfunctionalized olefins when the same
number of active methylene group equivalents are used
Experimental Section
Typical procedure for the cyclopropanation reaction using iodomethylzinc
2
,4,6-trichlorophenoxide: Et
solution of 2,4,6-trichlorophenol =0.197 g, 1.0 mmol) in CH
À408C. The solution was stirred for 15 min at that temperature and then
CH =81 mL, 1.0 mmol) was added. After stirring for an additional 15 min,
2
Zn =103 mL, 1.0 mmol) was added to
a
2
2
Cl =10 mL) at
2 2
I
a-methylstyrene =65 mL, 0.5 mmol) was added. The cold bath was removed
and the mixture was stirred for 12 h. Pentane =25 mL) was added and the
organic phase was washed sequentially with 10% aq HCl =2 Â 25 mL),
=
entry 6 versus 16 ± 18). The zinc phenoxide reagent is
[8]
typically more reactive than Furukawa et al.ꢁs reagent and
bis=iodomethyl)zinc and of comparable reactivity to Den-
mark and Edwardsꢁ bis=chloromethyl)zinc.[
saturated aq NaHCO
saturated aq NaCl =25 mL). The organic layer was dried over MgSO and
3
=2 Â 25 mL), saturated aq Na
2 3
SO =25 mL), and
4
9]
concentrated to approximately 300 mL under reduced pressure. Flash
chromatography =100% pentane) afforded the desired cyclopropane
In addition to aryl-substituted olefins, alkyl-substituted
alkenes are also converted into the corresponding cyclo-
propane in high yields =Table 2). The yields are excellent in all
1
=
=
62 mg, 94%) as
400 MHz, CDCl
a
colorless liquid:
R
f
ˆ 0.47 =pentane);
H NMR
3
): d ˆ 7.39 =m, 4H), 7.28 =m, 1H), 1.54 =s, 3H), 0.99 =dd,
13
J ˆ 5.9, 4.4 Hz, 2H), 0.85 =dd, J ˆ 6.1, 4.2 Hz, 2H); C NMR =100 MHz,
CDCl
C
C
3
): d ˆ 147.1, 128.3, 126.8, 125.5, 25.8, 19.8, 15.7; HR-MS: calcd for
10
H
H
12: 132.093900, found: 132.092033; elemental analysis: calcd for
12: C 90.85, H 9.15; found: C 90.87, H 9.30.
Table 2. Cyclopropanation of alkyl-substituted alkenes with2,4,6-
Cl C H OZnCH I.
3 6 4 2
10
Received: July 10, 2000
Revised: October 4, 2000 [Z15426]
[
1] For recent examples, see: callipeltoside A: A. Zampella, M. V.
DꢁAuria, L. Minale, C. Debitus, C. Roussakis, J. Am. Chem. Soc.
1
996, 118, 11085 ± 11088; bisgersolanolide: A. D. Rodríguez, J.-G. Shi,
Conversion [%][a]
Org. Lett. 1999, 1, 337 ± 340; quinoxapeptins A ± C: D. L. Boger, M. W.
Ledeboer, M. Kume, Q. Jin, Angew. Chem. 1999, 111, 2533 ± 2536;
Angew. Chem. Int. Ed. 1999, 38, 2424 ± 2426.
Entry
Alkene
1
2
3
> 95 =90)
> 95 =97)
> 95 =93)[b]
[
2] a) Y. Zhao, T.-F. Yang, M. Lee, B. K. Chun, J. Du, R. F. Schinazi, D.
Lee, M. G. Newton, C. K. Chu, Tetrahedron Lett. 1994, 35, 5405 ± 5408;
b) F. Cluet, A. Haudrechy, P. Le Ber, P. Sina yÈ , Synlett 1994, 913 ± 915;
c) J. B. Rodriguez, V. E. Marquez, M. C. Nicklaus, J. J. Barchi, Jr.,
Tetrahedron Lett. 1993, 34, 6233 ± 6236.
[
3] For excellent reviews, see: a) J. Salaün in Small Ring Compounds in
Organic Synthesis VI, Vol. 207 =Ed.: A. de Meijere), Springer, Berlin,
2000, pp. 1 ± 67; b) J. Salaün, Curr. Med. Chem. 1995, 2, 511 ± 542.
4] a) The Chemistry of the Cyclopropyl Group =Ed.: Z. Rappoport),
Wiley, Chichester, 1987; b) Small Ring Compounds in Organic
Synthesis VI, Vol. 207 =Ed.: A. de Meijere), Springer, Berlin, 2000,
and references therein; c) Methods Org. Chem. ꢀHouben-Weyl) 4th ed.
1952 ± , Vol. E17/c.
4
> 95 =96)
> 95 =98)
5[c]
6[c]
[
92 =92[d], 85[e]
)
[
a] Yields of isolated products are given in parentheses. [b] In this case,
3
equiv of the carbenoid were used. [c] Bn ˆ Benzyl. [d] 1 equiv of the
carbenoid was used =see text). [e] 4 equiv of the carbenoid was used =see
text).
[5] a) H. E. Simmons, R. D. Smith, J. Am. Chem. Soc. 1958, 80, 5323 ±
5324; b) H. E. Simmons, R. D. Smith, J. Am. Chem. Soc. 1959, 81,
4
256 ± 4264.
[
6] For a recent review, see: a) A. B. Charette in Organozinc Reagents. A
Practical Approach =Eds.: P. Knochel, P. Jones), Oxford University,
Oxford, 1999, pp. 263 ± 283; b) Methoden Org. Chem. ꢀHouben-Weyl)
cases. As observed withother zinc reagents, it is also possible
to achieve a chemoselective monocyclopropanation of an
allylic ether in the presence of a trisubstituted olefin when
only one equivalent of the reagent is used =entry 6). The use of
an excess of the reagent led to the dicyclopropane derivative.
Although we have not been able to characterize the reagent
by NMR spectroscopy yet, we have shown that a solution of
4
th ed. 1952 ± , Vol. E17/a,b.
[
7] a) For a review, see: H. E. Simmons, T. L. Cairns, S. A. Vladuchick,
C. M. Hoiness, Org. React. 1973, 20, 1 ± 131; b) W. B. Motherwell, C. J.
Nutley, Contemp. Org. Synth. 1994, 1, 219 ± 241.
[8] a) J. Furukawa, N. Kawabata, J. Nishimura, Tetrahedron Lett. 1966,
3353 ± 3354; b) J. Furukawa, N. Kawabata, J. Nishimura, Tetrahedron
1
968, 24, 53 ± 58.
2
,4,6-Cl C H OZnCH I in CH Cl is stable for at least one
3 6 2 2 2 2
[
9] S. E. Denmark, J. P. Edwards, J. Org. Chem. 1991, 56, 6974 ± 6981.
hour at 08C, which indicates that the reagent is quite stable.
However, a significant drop in the yield was observed when a
solution of the reagent that was four hours old was used.
[
[
10] A. B. Charette, C. Brochu, J. Am. Chem. Soc. 1995, 117, 11367 ± 11368.
11] Z. Q. Yang, J. C. Lorenz, Y. Shi, Tetrahedron Lett. 1998, 39, 8621 ±
8624.
Angew. Chem. Int. Ed. 2000, 39, No. 24
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[
12] Several solvents were tested and noncomplexing solvents, suchas
dichloromethane or 1,2-dichloroethane, were optimal.
13] E. K. Lehnert, J. S. Sawyer, T. L. Macdonald, Tetrahedron Lett. 1989,
Researchon luminescent lant ha nide complexes ha s been
almost exclusively devoted to europium=iii) and terbium=iii)
[
complexes.[
6±8]
The energetics of sensitized luminescence,
3
0, 5215 ± 5218.
however, dictate that those complexes must be excited with
ultraviolet light,[ which is not desirable when working with
vital biosystems, requires special optics, and causes extensive
scattering in inhomogeneous media. Although some recent
work has demonstrated that the excitation window for Eu
complexes can be extended to the violet edge of the visible
[
14] Preliminary results indicate that the use of chiral phenols is possible.
Enantioselectivities of the reaction involving these chiral reagents are
encouraging. For example, the reagent derived from the monobenzyl
ether of 3,3'-dimethylbinaphthol converted the benzyl ether of
cinnamyl alcohol into the corresponding cyclopropane with 33% ee.
15] Katsuki and co-workers have recently reported the use of a 3,3'-
disubstituted binaphthol to perform the enantioselective cyclopropa-
9]
III
[
region[ or even to the blue region, it would be desirable to
use significantly longer wavelengths for excitation. Lantha-
nide ions that emit in the near-infrared, such as ytterbiu-
10]
[11]
nation of allylic alcohols but six equivalents of Et
equivalent of phenol =threefold excess). Free EtZnCH
formed in this system =and not ArOZnCH I): H. Kitajima, K. Ito, Y.
Aoki, T. Katsuki, Bull. Chem. Soc. Jpn. 1997, 70, 207 ± 217.
2
Zn were used per
2
I is presumably
2
m=iii),[ neodymium=iii), and erbium=iii), may be excited
through organic dyes that absorb at wavelengths extending
towards the red region of the spectrum. With their potential
use as luminescent labels in mind we designed and studied
well-defined, water-soluble near-infrared luminescent lantha-
nide complexes containing organic dyes as the light-absorbing
unit.[ Recently, we found that 4',5'-bis[N,N-bis=carboxyme-
thyl)aminomethyl]-fluorescein =fluorexon, Fx) is a very
efficient sensitizer and a strongly binding ligand for near-
12]
[13]
14]
A Near-Infrared Luminescent Label Based on
III
Yb Ions and Its Application in a
Fluoroimmunoassay**
[15]
infrared-luminescent lanthanide ions. The thermodynamic
stability of the [Yb=Fx)] complex is comparable to that of
Martinus H. V. Werts, Richard H. Woudenberg,
Peter G. Emmerink, Rob van Gassel,
Johannes W. Hofstraat, and Jan W. Verhoeven*
[Yb=EDTA)] =EDTA ˆ ethylenediaminetetraacetate).
Here we report on the ligand FxITC =5; Scheme 1), which is
structurally similar to Fx but carries an isothiocyanate group
=ITC) that is reactive towards amine groups and so can be
coupled to proteins. The iminodiacetic acid groups ensure
firm complexation of lanthanide ions =like they do in
[Yb=Fx)]), and the dichlorofluorescein chromophore acts as
a sensitizer to near-infrared lanthanide luminescence.
There has been a great deal of interest in luminescent
lanthanide complexes since Weissmanꢁs discovery that in
these complexes ªthe excitation may be accomplished, under
suitable conditions, through light absorption by other con-
stituents of the rare earth compound with subsequent transfer
of energy to the rare earth ionº.[ The energy transfer from
organic chromophores to lanthanide ions that he described
provides an effective way to excite the long-lived, sharply
spiked emission. Direct excitation of lanthanide ions is
difficult because of the forbidden nature of the electronic
transitions in these ions. One of the most important applica-
tions of lanthanide complexes is as luminescent labels in
clinical diagnostics where they provide an alternative to
radioactive probes.[ Since lanthanide luminescence decays
much more slowly than the autofluorescence from the bio-
logical material, the latter is suppressed when using time-
gated detection.
1]
The synthesis of FxITC =Scheme 1) reflects the idea of
[16]
combining the syntheses of Fx and fluorescein isothiocya-
nate.[ 2',7'-Dichloro-4-nitrofluorescein diacetate was ob-
tained by condensing 4-nitrophthalic acid with 4-chlororesor-
cinol at 2408C and was separated from the 5-nitro isomer by
fractional crystallization from acetic acid.[ The dichloro
derivative was chosen to prevent formation of isomers during
the introduction of the methyleneiminodiacetic acid groups.
Moreover, the ªheavyº chlorine atoms might enhance inter-
system crossing in the chromophore which is favorable for
sensitizing lanthanide luminescence.[
17]
18]
2±5]
15]
Direct introduction of the methyleneiminodiacetic acid
[16]
groups, as used in the production of Fx, was not successful.
Reaction of iminodiacetic acid dimethyl ester[ with 2 and
19]
[20]
[
*] Prof. Dr. J. W. Verhoeven, M. H. V. Werts
Laboratory of Organic Chemistry
subsequent hydrolysis of the ester yielded 3, the desired nitro
University of Amsterdam
precursor to FxITC. Reduction of 3 using H /Raney Ni
proceded cleanly, but gave rise to the dinickel complex of 4,
which can be observed with electrospray mass spectrometry.
2
Nieuwe Achtergracht 129, 1018 WS Amsterdam =The Netherlands)
Fax : =‡31)20-525-5670
E-mail: jwv@org.chem.uva.nl
Therefore, 3 was reduced using Na S/NaHS in dilute NaOH.
2
Dr. R. H. Woudenberg, P. G. Emmerink, R. van Gassel
Akzo Nobel Central Research
After purification by preparative HPLC =C column, eluent:
8
P.O. Box 2300, 6800 SB Arnhem =The Netherlands)
water:acetonitrile:formic acid =155:45:1)), 4 was converted
into FxITC using thiophosgene in acetone.
Prof. Dr. J. W. Hofstraat
Philips Research, Prof. Holstlaan 4
The isopropylamine adduct 6 shows the same complexation
5
656 AA Eindhoven =The Netherlands)
[15]
behavior towards lanthanide ions as Fx does. Fluorimetric
[
**] This work was supported by Akzo Nobel Central Research =Arnhem,
The Netherlands). Dr. Fokke Venema and Dr. Harrie Kreuwel of
Organon Teknika B.V. =Boxtel, The Netherlands) are gratefully
acknowledged for discussions and suggestions regarding the diagnos-
tic test, and for supplying the immunochemicals.
III
titrations withYb ions indicate formation of a 1:1 complex
III
as long as there is no excess Yb ions. Excess lanthanide ions
leads to the formation of poorly emitting aggregates that so
far have escaped further characterization. Such aggregates,
4542
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1433-7851/00/3924-4542 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2000, 39, No. 24