Preparation of 2-magnesiated 1,3,5-triazines via an iodine-magnesium exchange

Article abstract of DOI:10.1021/ol102173z

Functionalized iodo- and diiodo-1,3,5-triazine derivatives readily undergo an I/Mg exchange with BuMgCl, sBuMgCl, or OctMgBr at low temperatures furnishing 2-magnesiated and 2-zincated 1,3,5-triazines (after transmetalation with ZnCl₂). This me

Full text of DOI:10.1021/ol102173z

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5398-5401
Preparation of 2-Magnesiated
1,3,5-Triazines via an
Iodine-Magnesium Exchange
Zhihua Peng, Benjamin A. Haag, and Paul Knochel*
Department Chemie, Ludwig-Maximilians-UniVersita¨t Mu¨nchen, Butenandtstr. 5-13,
Haus F, 81377 Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received September 10, 2010
ABSTRACT
Functionalized iodo- and diiodo-1,3,5-triazine derivatives readily undergo an I/Mg exchange with BuMgCl, sBuMgCl, or OctMgBr at low temperatures
furnishing 2-magnesiated and 2-zincated 1,3,5-triazines (after transmetalation with ZnCl2). This method also offers a convenient access to
dimagnesiated triazines. Furthermore, it allows the preparation of functionalized 1,3,5-triazinyl dimers and trimers, interesting for their opto-
electronic properties.
Heterocycles have gained increased significance in modern
chemistry.1 Among N-containing heterocycles, 1,3,5-triazine
derivatives2,3 have found numerous industrial applications
as pharmaceuticals,4 liquid crystals,5 reactive dyes,6 and
organic light-emitting diodes (OLEDs).7 However, the ef-
ficient syntheses of polyfunctional 1,3,5-triazines, including
dimeric and trimeric triazine derivatives, remain a synthetic
challenge. Metalated heterocyclic intermediates have proven
to possess great potential for the concise synthesis of
functionalized heterocycles.8 Especially polyfunctionalized
organomagnesium compounds show a high tolerance toward
a wide range of functional groups and are easily accessible,
e.g., via Br/Mg or I/Mg exchange reaction.9 It has been
reported that the reactions of 2-chloro-4,6-dimethoxy-1,3,5-
triazine with ketones using lithium powder and substoichio-
metric amounts of naphthalene involving a lithiated 1,3,5-
triazine intermediate afford the corresponding alcohols in
13-50% yield.10 Herein, we report a straightforward and
(1) (a) Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R. In
Heterocycles in Life and Society; Wiley-VCH: Weinheim, 1997. (b) Eicher,
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(b) Ronchi, S.; Prosperi, D.; Compostella, F.; Panza, L. Synlett 2004, 1007.
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2000, 65, 8108. (b) Poirier, M.; Chen, F.; Bernard, C.; Wong, Y.-S.; Wu,
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10.1021/ol102173z  2010 American Chemical Society
Published on Web 11/02/2010

practical preparation of fully substituted 1,3,5-triazines via
magnesiated triazines as well as synthetic routes to highly
functionalized 1,3,5-triazine dimers and trimers which are
expected to be valuable advanced materials. Thus, various
functionalized iodotriazine derivatives of type 1 underwent a
smooth I/Mg exchange reaction using BuMgCl (2a) or Oct-
MgBr (2b; 1.1 equiv, -78 °C, 10 min) affording the corre-
sponding 2-magnesiated 1,3,5-triazines of type 3 (Scheme 1).
equiv, -20 °C, 30 min) undergoes a cross-coupling with
ethyl 4-iodobenzoate (4a) in the presence of Pd(dba)2 (5
mol %) and tfp14 () P(2-furyl)3; 10 mol %), affording
the trisubstituted 1,3,5-triazine derivative 5a in 62% yield
(entry 1, Table 1). Additionally, a copper-catalyzed
allylation15 (CuCN·2LiCl, 20 mol %) of 3a with ethyl (2-
bromomethyl)acrylate16 (4b) produced the acrylate 5b in
73% yield (entry 2). In the same manner, a range of 1,3,5-
triazinylmagnesium reagents bearing electron-donating
functional groups such as a 2-thienyl group (3b), a
diphenylamino group (3c), or an aryl group bearing
various substituents (3d-j) were prepared by reaction with
BuMgCl (2a) or OctMgBr (2b; 1.1 equiv, -78 °C, 10
min) with 2-iodo-1,3,5-triazine derivatives (1a-j). The
resulting 1,3,5-triazinylmagnesium reagents 3b-j reacted
with various electrophiles 4b-e affording the fully
substituted 1,3,5-triazines 5c-m in 59-75% yield (entries
3-13). Thus, a Cu(I)-catalyzed allylation (CuCN·2LiCl,
20 mol %) of the magnesiated triazine 3b with ethyl
2-(bromomethyl)acrylate16 (4b) furnished the trisubstituted
acrylate 5c in 59% yield (entry 3). Similarly, the mag-
nesium reagent 3c afforded, after a Cu(I)-mediated ben-
zoylation with 4c (CuCN·2LiCl, 1.1 equiv), the triazinyl
ketone 5d in 71% yield (entry 4). Moreover, the substi-
tuted 2-triazinyl alcohol 5e was obtained after addition
of the organomagnesium reagent 3d to PhCHO (4d) in
61% yield (entry 5). Remarkably, also electron-poor
triazines 1e,f underwent a smooth I/Mg-exchange with
BuMgCl (2a; 1.1 equiv, -78 °C, 10 min) affording the
functionalized 1,3,5-triazinylmagnesium reagents 3e,f.
Subsequent Cu(I)-catalyzed allylation (CuCN·2LiCl, 20
mol %) with ethyl 2-(bromomethyl)acrylate16 (4b) or
addition to PhCHO (4d) afforded the trisubstituted 1,3,5-
triazines 5f and 5g in 54-71% yield (entries 6 and 7).
The 1,3,5-triazine-based Grignard reagents 3g-j bearing
electron-withdrawing functional groups such as ester,
cyano, and halo groups in the ortho- or para-position of
the phenyl substituent were prepared via a rapid I/Mg
exchange with OctMgBr (2b; 1.1 equiv, -78 °C, 10 min)
from the corresponding substituted 2-iodo-1,3,5-triazines
1g-j. In comparison to BuMgCl (2a), OctMgBr (2b)
avoids side products due to a nucleophilic substitution of
the triazine ring. Thus, the 1,3,5-triazinylmagnesium
Scheme 1. Preparation of Functionalized
1,3,5-Triazinylmagnesium Reagents of Type 3 and
Functionalization with Various Electrophiles
Subsequent reactions of the triazinylmagnesium reagents 3 with
various electrophiles (E+; 4a-e) led to substituted triazines of
type 5 in 59-75% yield (Scheme 1 and Table 1).
In comparison to well-established Hal/Mg exchange
reagents such as iPrMgCl,11 the Grignard reagents BuMgCl
(2a) and OctMgBr (2b) are less nucleophilic and more
selective, avoiding undesired substitution products. The
substrates for the exchange reactions, namely, the iodotriazine
derivatives of type 1, were prepared from 2,4-diiodo-6-
phenyl-1,3,5-triazine12 (6) using Negishi-type cross-cou-
plings13 with functionalized organozinc reagents in the
presence of Pd(PPh3)2Cl2 (1 mol %) in 47-80% yield
(Scheme 1).
The reaction of 6-iodo-4-octyl-2-phenyl-1,3,5-triazine
(1a) with BuMgCl (2a; 1.1 equiv, -78 °C, 10 min)
provided the corresponding triazinylmagnesium chloride
(3a), which after transmetalation with ZnBr2·LiCl (1.1
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Org. Lett., Vol. 12, No. 23, 2010
5399

Table 1. Functionalized 1,3,5-Triazine Derivatives of Type 5 Obtained by I/Mg Exchange and Subsequent Quenching with an
Electrophile
a Isolated yield of analytically pure product. b Obtained after I/Mg exchange with BuMgCl (2a; -78 °C, 10 min). c Obtained after I/Mg- exchange with
OctMgBr (2b; -78 °C, 10 min). d Obtained after transmetalation with ZnBr2·LiCl (1.1 equiv) and subsequent Negishi cross-coupling13 with ethyl 4-iodobenzoate
in the presence of Pd(dba)2 (5 mol %) and tfp (10 mol %). e Obtained after addition of CuCN·2LiCl (20 mol %). f Obtained after transmetalation with
CuCN·2LiCl (1.1 equiv).
reagent 3g afforded, after addition to PhCHO (4d) or
p-NC-C6H4CHO (4e), the functionalized 1,3,5-triazinyl
alcohols 5h,i in 63-75% yield (entries 8 and 9). Similarly,
a Cu-catalyzed allylation of 3g provided the triazinyl-
substituted acrylate 5j in 71% yield (entry 10). The
ethoxycarbonyl-, bromo-, and cyano-substituted triazinyl-
magnesium reagents 3h-j underwent similar additions to
PhCHO (4d) or Cu-mediated benzoylation with PhCOCl
(4c), leading to trisubstituted 1,3,5-triazine derivatives
5k-m in 63-68% yield (entries 11-13).
In general, the preparation of bis-magnesiated aromatics
requires harsh reaction conditions, and only a few examples
have been reported.17 However, the I/Mg exchange of 2,4-
diiodo-1,3,5-triazine (6) with sBuMgCl (2c; 2.2 equiv, -78
°C, 10 min) readily furnished the doubly magnesiated 1,3,5-
triazine 7 (>90% yield18).
5400
Org. Lett., Vol. 12, No. 23, 2010

Transmetalation of 7 with CuCN·2LiCl (2.2 equiv, -78
to -40 °C) afforded the biscopper derivatives which after
allylation or acylation produced the bis-functionalized tri-
azines 9 and 10 in yields of 67% and 38%, respectively
(Scheme 2). Conjugated molecules bearing 1,3,5-triazine
Scheme 3
.
Preparation of Dimeric and Trimeric Triazines
11-13
Scheme 2
.
Preparation of the Dimagnesiated 1,3,5-Triazine
Derivatives 9 and 10
The trimeric triazine derivative 13 was prepared from the
iodotriazine 1g by I/Mg exchange and transmetalation with
ZnCl2, leading to the zinc reagent 17 (>90% yield18). Negishi
cross-coupling of 17 with 2,4-diiodo-6-phenyl-1,3,5-triazine
(6) in the presence of Pd-PEPPSI-IPr20 (5 mol %, 25 °C,
24 h) affords the triazine 13 in 45% yield (Scheme 3).
In summary, we have developed a new method for the
preparation of stable mono- and bis(1,3,5-triazinyl)magne-
sium reagents, which react with aldehydes, acid clorides, and
allylic halides, furnishing a wide range of new functionalized
fully substituted 1,3,5-triazine derivatives. Remarkably,
dimeric and trimeric triazine derivatives were also prepared
using triazinylzincs as key intermediates. Further investiga-
tions of these reagents and functionalized, fully substituted
products, especially toward applications as opto-electronic
materials, are currently underway in our laboratories.
moieties may exhibit useful opto-electronic properties.19 We
have used the functionalized triazinylmagnesium reagents
of type 3 for the syntheses of trimeric and dimeric derivatives
11-13 (Scheme 3). Thus, 2-iodo-4,6-diphenyl-1,3,5-triazine
(1d) undergoes a smooth I/Mg exchange with BuMgCl (2a;
1.1 equiv, -78 °C, 10 min) and leads after a transmetalation
with ZnCl2 (1.05 equiv, -78 °C, 10 min) to the correspond-
ing 1,3,5-triazinylzinc chloride 14 (>90% yield18). Subse-
quent Pd(0)-catalyzed cross-coupling13 with the iodotriazine
1d (1.0 equiv, -78 to 25 °C, 24 h) provided the dimeric
triazine 11 in 57% yield (Scheme 3). Similarly, the I/Mg
exchange reaction of 2-iodo-4-(4-butylphenyl)-6-phenyl-
1,3,5-triazine (15) with sBuMgCl (2c; 1.1 equiv, -78 °C,
10 min) followed by ZnCl2 addition furnished the 1,3,5-
triazinylzinc reagent 16. Subsequent Negishi cross-coupling13
with 1g (1.0 equiv) using Pd-PEPPSI-IPr20 (5 mol %, 25 °C,
24 h) led to the dimeric triazine 12 in 52% yield (Scheme 3).
Acknowledgment. We thank the European Research
Council (ERC) for financial support. We thank Prof. Thomas
Bein for fruitful discussions. We also thank W. C. Heraeus
(Hanau), Chemetall (Frankfurt), and BASF AG (Ludwig-
shafen) for the generous gift of chemicals.
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Supporting Information Available: Experimental pro-
cedures and characterization data of all compounds are
provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL102173Z
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