A general method for meta and para functionalization of arenes using TMP2Mg·2 LiCl

Article abstract of DOI:10.1002/anie.200703382

(Chemical Equation Presented) Getting directions: The (Me ₂N)₂P(O)O substituent serves as an effective directing-metalation group in the magnesiation of substituted arenes with TMP₂Mg·2 LiCl (see scheme). This reaction can

Full text of DOI:10.1002/anie.200703382

Angewandte
Chemie
DOI: 10.1002/anie.200703382
Grignard Reactions
A General Method for meta and para Functionalization of Arenes
Using TMP2Mg·2LiCl**
Christoph J. Rohbogner, Giuliano C. Clososki, and Paul Knochel*
ortho-Directed metalation is an important method for the
functionalization of various arenes and heterocycles. Various
directed-metalation groups (DMGs) have been used for
achieving efficient lithiations.[1] DMGs mediate fast and
ortho-selective metalation mainly by chelation (entropic
effect). Polar DMGs may furthermore transfer electron
density to the metal base and increase their metalating
power.[2] Recently, magnesiate bases have proven to be of
great structural and synthetic interest for the functionaliza-
tion of arenes.[3] Alternatively, we have shown that the mixed
Li/Mg bases TMPMgCl·LiCl (1)[4] and TMP2Mg·2LiCl (2;
TMP = 2,2,6,6-tetramethylpiperamidyl)[5] are highly active
and soluble magnesium bases that allow smooth metalation
Scheme 1. meta,para and para,meta functionalization using
TMP2Mg·2LiCl.
of various arenes and heterocycles with an excellent func-
tional-group compatibility.[4–6]
In the course of these studies we observed that the DMG
N,N,N’,N’-tetramethylphosphorodiamidate ((Me2N)2P(O)-
O-)[7] is a very strong directing group for magnesiation and
that it may overrule the effects of other substituents present
on the aromatic substrate. In contrast to directed lithiations,
which are usually performed at À1058C to avoid Fries-type
rearrangements,[7] the magnesiation with TMP2Mg·2LiCl
occurs (even at 08C) without anionic migration of the
tetramethylphosphorodiamidate group. This would allow
new types of functionalization such as formal meta[8] or para
functionalization (Scheme 1). Thus, we have found that a
range of aromatic phosphorodiamidates bearing a functional
group (FG) either in the para position (type 3) or in the meta
position (type 4) undergo efficient magnesiation with
TMP2Mg·2LiCl (2) leading to products of type 5 and 6,
respectively, after the addition of an electrophile. Substitution
of the OP(O)(NMe2)2 group with a nucleophile (Nu) gives
meta,para- and para,meta-difunctionalized molecules of types
7 and 8 as described below (Scheme 1 and Table 1). The
magnesiation of substrates 3 and 4 using TMP2Mg·2LiCl (2)
proceeds smoothly within a few hours at 08C for cyano- and
ester-substituted phosphorodiamidates 3a and 4a (entries 1–3
and 10–13, Table 1). For halogen-substituted starting materi-
als (3b–d; entries 4–9. Table 1) as well as for the trifluor-
omethyl-substituted phosphorodiamidate 4b (entry 14),
lower temperatures (À40 to À508C) led to optimum results.
In general, the regioselectivity of arene metalation is
governed by a combination of electronic and/or steric
effects.[1,2] The tetramethylphosphorodiamidate group, one
of the strongest donors in organic synthesis,[9] activates the
[3,10]
À
Mg N bond giving the base ate character (Scheme 2).
Scheme 2. The ate character of TMP2Mg·2LiCl (2) induces efficient
para metalation. (LiCl has been omitted for clarity.)
This electronic effect increases the metalation power of the
base, and no additional chelation or inductive effects are
necessary for achieving the magnesiation. Normally, this
phosphorodiamidate-triggered magnesiation occurs prefer-
entially at the sterically less hindered position of the arene
ring, promoting formally meta metalation. However, in the
case of meta-substituted substrates bearing bromo, chloro,
and fluoro functional groups, we observed that the regiose-
lectivity of the metalation is affected[11] by the competitive
directing effects of these halogens.
[*] Dipl.-Chem. C. J. Rohbogner, Dr. G. C. Clososki, Prof. Dr. P. Knochel
Ludwig-Maximilians-Universität München
Department Chemie und Biochemie
Butenandtstrasse 5–13, Haus F, 81377 München (Germany)
Fax: (+49)89-2180-77680
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank the Fonds der Chemischen Industrie and the Deutsche
Forschungsgemeinschaft (DFG) for financial support. G.C. thanks
the Humboldt Foundation for a fellowship. We also thank Chemetall
GmbH (Frankfurt), Evonik Industries AG (Essen), and BASF AG
(Ludwigshafen) for generous gifts of chemicals.
Various electrophiles such as acid chlorides, TsCN, allylic
halides, aldehydes, and aryl iodides react with the organo-
magnesium intermediates providing the desired products in
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Products of types 5 and 6 obtained by direct magnesiation of phosphoroamidates 3 and 4 with
(TMP)2Mg·2LiCl (2) followed by the reaction with electrophiles.
72–90% yields (Table 1). In the
case of allylation and acylation
reactions, the best results were
obtained when the aryl magnesium
species were transmetalated with
ZnCl2 (1.2 equiv) and CuCN·2LiCl
(0.5–1.3 equiv)[12] prior to the addi-
tion of the acid chloride, TsCN, or
the allylic halide (entries 2–4, 7, 8,
and 12, Table 1). Similarly, Negishi
cross-couplings[13] with aryl iodides
in the presence of [Pd(dba)2]
(2 mol%; dba = dibenzylideneace-
tone) and P(2-fur)3 (4 mol%; fur=
furfuryl)[14] were successfully per-
formed after transmetalation of the
Grignard reagents with ZnCl2
(entries 1, 5, 6, and 13, Table 1).
Double functionalization in the
Entry Substrate
T [oC],t [h] EX[a]
Product
Yield [%][b]
1
2
3
3a
3a
3a
0, 1
0, 1
0, 1
p-IC6H4OTIPS
TsCN
5d: E=p-C6H4OTIPS
5e: E=CN
83[c]
77[d]
CH2 C(CH3)CH2Br 5 f: E=CH2 C(CH3)CH2 84[d]
=
=
4
3b
À50, 7
tBuCH2COCl
5g
72[d]
meta,meta’ positions has also been
achieved. Thus, the treatment of the
nitrile 3a with TMP2Mg·2LiCl
(1.1 equiv, 08C, 1 h) followed by a
copper(I)-catalyzed reaction with
tBuCOCl provides the ketone 5a
in 81% yield (Scheme 3). Applica-
tion of the same reaction sequence
(metalation at À608C for 0.5 h)
converted ketone 5a into the dike-
tone 9a in 77% yield. Furthermore,
the double functionalization of the
bromo- and chloro-substituted
phosphorodiamidates 3b and 3d
led to the preparation of the highly
5
6
7
3c
3c
3c
À40, 4
À40, 4
À40, 4
p-IC6H4CO2Et
m-CH3C6H4I
c-C6H9Br
5h: E=p-C6H4CO2Et
5i: E=m-CH3C6H4
5j: E=c-C6H9
78[c]
75[c]
85[d]
8
9
3d
3d
À40, 1.5
À40, 1.5
PhCOCl
tBuCHO
5k: E=COPh
5l: E=tBuC(OH)
85[d]
79
functionalized
phosphorodiami-
dates 9b and 9c, respectively, in
good overall yields (Scheme 3).
This demonstrates the high direct-
ing power of the OP(O)(NMe2)2
group.
10
12
13
4a
4a
4a
0, 1
0, 1
0, 1
(BrCl2C)2
PhCOCl
p-IC6H4CO2Et
6a: E=Br
6b: E=COPh
6c: E=p-C6H4CO2Et
80
73[d]
78[c]
Further manipulation of the
functionalized aryl phosphorodia-
midates of types 5 and 6 was best
achieved by converting these inter-
mediates into nonaflates[15] or tri-
flates. Thus, microwave-assisted
deprotection of aryl phosphorodia-
midates 5b and 5c with formic acid
in aqueous ethanol (1208C, 30 min)
provided polyfunctional phenols,
which after the reaction with
C4F9SO2F (NaH, Et2O, 25 8C, 12 h)
provided the corresponding nona-
flates 11a and 11b in 71% yield
14
15
4b
4c
À40, 2
I2
6d
6e
88
76
0, 0.5
(BrCl2C)2
[a] TIPS=triisopropylsilyl; Ts=p-toluenesulfonyl. [b] Yield of isolated, analytically pure product.
[c] Obtained by palladium-catalyzed cross-coupling after transmetalation with ZnCl2 (1.2 equiv). [d] A
transmetalation with ZnCl2 (1.2 equiv) and CuCN·2LiCl (0.5–1.3 equiv) was performed.
(Scheme 4).
A
nickel-catalyzed
cross-coupling of nonaflate 11a
with the arylzinc reagent 13
afforded the biphenyl 12a in 90%
yield. On the other hand, reaction
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Scheme 3. Double functionalization of phosphorodiamidates 3a, 3b, and 3d, leading to meta,meta’-substituted products 9a–c.
Scheme 4. Microwave-assisted deprotection of the aryl phosphorodiamidates for further functionalization or DMG removal. NEP=N-ethyl-
pyrrolidone.
of 11b with dimethylamine–borane complex in the presence
of a catalytic amount of [Pd(PPh3)4][16] gave the reduced
derivative 12b in 94% yield. Similarly, the aryl phosphor-
odiamidate 6b was successfully converted to the diester 12c
and to the keto ester 12d in 95% and 74% yield, respectively,
showing that this reaction sequence allows efficient function-
alization as well as removal of the directing metalation group
(Scheme 4).
In summary, we have reported a method that leads to
arenes with new functionalization patterns through magne-
siations with the powerful TMP2Mg·2LiCl base (2) combined
with the phosphorodiamidate (OP(O)(NMe2)2) as a strong
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Organolithium Compounds (Eds.: Z. Rappoport, I. Marek),
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metalation-directing group. This methodology allows the
general preparation of various meta,para- and meta,meta’-
polyfunctionalized arenes, which are not easily accessible by
conventional synthetic strategies. Applications toward the
synthesis of biologically active molecules are currently being
investigated in our laboratories.
Experimental Section
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Synthesis of 2: In
a dry argon-flushed Schlenk tube, 2,2,6,6-
tetramethylpiperidine (TMPH; 5.07 mL, 30 mmol) was dissolved in
THF (30 mL). This solution was cooled to À408C, and nBuLi (2.4m in
hexane, 12.5 mL, 30 mmol) was added dropwise. After the addition
was complete, the reaction mixture was warmed to 08C and stirred at
this temperature for 30 min. Freshly titrated TMPMgCl·LiCl (1)[4] (1m
in THF, 30 mL, 30 mmol) was then added dropwise to the LiTMP
solution, and the reaction mixture was stirred at 08C for 30 min,
warmed to 258C, and stirred for 1 h. The solvents were then removed
in vacuo without heating, affording a yellowish solid. Freshly distilled
THF was slowly added with vigorous stirring, until the salts had
completely dissolved. The fresh TMP2Mg·2LiCl solution was
titrated[17] prior to use at 08C with benzoic acid using 4-(phenyl-
azo)diphenylamine as indicator. A concentration of 0.6m in THF was
obtained.
Synthesis of 5c: In a dry argon-flushed Schlenk tube the aryl
phosphorodiamidate 3d (2.62 g, 8.00 mmol) was dissolved in THF
(8 mL) and cooled to À408C, and TMP2Mg·2LiCl (0.6m in THF,
14.7 mL, 8.8 mmol) was added dropwise. The mixture was stirred at
À408C for 1.5 h. Complete metalation was detected by GC analysis of
reaction aliquots, which were quenched with I2 in anhydrous THF. A
solution of ZnCl2 (1m in THF, 9.6 mL, 9.6 mmol) was added dropwise,
and the resulting mixture was stirred for 15 min. First a solution of
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[Pd(dba)2](88 mg, 2 mol%) and P(2-fur) (72 mg, 4 mol%) in THF
3
(8 mL) then 4-iodoanisole (2.06 g, 8.8 mmol) was added, and the
reaction mixture was allowed to warm to room temperature. After
stirring for 12 h, the reaction mixture was quenched with aq. sat.
NH4Cl solution (20 mL) and extracted with diethyl ether (3 ” 50 mL)
then the aqueous phase was extracted with EtOAc (2 ” 50 mL). The
combined organic layers were washed with brine, dried over MgSO4,
filtered, and concentrated in vacuo. Purification by flash chromatog-
raphy on silica gel (ethyl acetate) furnished 5c (2.78 g, 90% yield) as
an orange oil.
Received: July 27, 2007
Revised: October 30, 2007
Published online: January 18, 2008
Keywords: arenes · directed metalation · Grignard reagents ·
.
magnesium bisamides · phosphorodiamidates
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tetramethyldiamidophosphate (43% yield). For the 3-chloro-
phenol derivative, a mixture of 5-chloro-2-iodophenyl- (29%
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