Mild iodine-magnesium exchange of iodoaromatics bearing a pyrimidine ring with isopropylmagnesium chloride

Article abstract of DOI:10.1021/ol061156s

Iodoaromatics bearing a reactive pyrimidine ring underwent a clean iodine-magnesium exchange with isopropylmagnesium chloride in the presence of bis[2-(N,N-dimethylamino)ethyl] ether to provide the corresponding Grignard reagents. The presence of bis[2-(N

Full text of DOI:10.1021/ol061156s

ORGANIC
LETTERS
2006
Vol. 8, No. 14
3141-3144
Mild Iodine−Magnesium Exchange of
Iodoaromatics Bearing a Pyrimidine
Ring with Isopropylmagnesium Chloride
Xiao-jun Wang,* Yibo Xu, Li Zhang, Dhileepkumar Krishnamurthy, and
Chris H. Senanayake
Department of Chemical DeVelopment, Boehringer Ingelheim Pharmaceuticals Inc.,
Ridgefield, Connecticut 06877
xwang@rdg.boehringer-ingelheim.com
Received May 11, 2006
ABSTRACT
Iodoaromatics bearing a reactive pyrimidine ring underwent a clean iodine−magnesium exchange with isopropylmagnesium chloride in the
presence of bis[2-(N,N-dimethylamino)ethyl] ether to provide the corresponding Grignard reagents. The presence of bis[2-(N,N-dimethylamino)-
ethyl] ether prevented reduction of the pyrimidine ring and addition by isopropylmagnesium chloride. As a result, the newly formed reactive
Grignard reagents were allowed to react with electrophiles in a highly selective manner to afford adducts in excellent yields.
The halogen-metal exchange has become a general and
chemoselective method for the preparation of functionalized
arylmagnesium reagents of considerable synthetic utility.1
This method tolerates a wide range of sensitive functional
groups such as ester and cyano groups.2 An iodine-
magnesium exchange reaction was attempted during the
development of a process for structurally complex nonpep-
tidic LFA-1 inhibitors3 bearing a sensitive pyrimidine ring.
Addition of organolithum and magnesium reagents to pyri-
midines is well-known to provide dihydropyrimidines.4 The
reactivity of the pyrimidine ring toward organomagnesium
reagents presented a major obstacle for the application of
iodine-magnesium exchange to our substrate. In this letter
we wish to report the first highly selective iodine-
magnesium exchange of iodoaromatics bearing a reactive
pyrimidine ring with i-PrMgCl-bis(2-dimethylaminoethyl)
ether complex and subsequent addition to electrophiles.5
Most iodine-magnesium exchanges are performed under
cryogenic conditions (<-20 °C) to suppress the competing
side reactions of sensitive functional groups. Following this
path, iodoimidazoles 1a,b were treated first with i-PrMgCl
in THF at -20 °C. The exchange reached >97% conversion
with the addition of a 30% excess of i-PrMgCl (Scheme 1).
In addition to the desired 2a,b (∼70%),6 3a,b also were
isolated (∼20%). Clearly, the iodine-magnesium exchange
was in competition with the attack of i-PrMgCl to the
pyrimidine ring. It is interesting to note that byproducts 4a,b
(∼10%) also formed due to reduction of the pyrimidine ring.
Considering the fact that the pyrimidine ring is electron
deficient, reduction of primidines by a hydride reagent is
(1) For a review, see: Knochel, P.; Dohle, W.; Gommermann, N.;
Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem.,
Int. Ed. 2003, 42, 4302.
(2) (a) Knochel, P.; Krasovskiy, A. Angew. Chem., Int. Ed. 2004, 43,
3333. (b) Yang, X.; Rotter, T.; Piazza, C.; Knochel, P. Org. Lett. 2003, 5,
1229. (c) Abarbri, M.; Thibonnet, J.; Berillon, L.; Dehmel, F.; Rottlander,
M.; Knochel, P. J. Org. Chem. 2000, 65, 4618.
(3) (a) Last-Barney, K.; Davidson, W.; Cardozo, M.; Frye, L. L.; Grygon,
C. A.; Hopkins, J. L.; Jeanfavre, D. D.; Pav, S.; Qian, C.; Stevenson, J.
M.; Tong, L.; Zindell, R.; Kelly, T. A. J. Am. Chem. Soc. 2001, 123, 5643.(b)
Wu, J.-P.; Kelly, T. A.; Lemieux, R.; Goldberg, D. R.; Emeigh, J. E.; Sorcek,
R. J. U.S. Patent WO-2001007440, 2001.
(4) For examples see: (a) Samaritoni, J. G.; Babbiu, G. F. J. Heterocycl.
Chem. 1997, 34, 1263. (b) Epifani, E.; Florio, S.; Ingrosso, G.; Babudri, F.
Tetrahedron 1989, 45, 2075. (c) Uno, H.; Terakawa, T.; Suzuki, H. Synthesis
1989, 381.
(5) (a) Shimura, A.; Momotake, A.; Togo, H.; Yokoyama, M. Synthesis
1999, 495. (b) Tanji, K.; Kato, H.; Higashino, T. Chem. Pharm. Bull. 1991,
39, 3037.
(6) All exchange reactions were monitored by HPLC for a convenient
analysis of product distribution of 2, 3, and 4.
10.1021/ol061156s CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/17/2006

Scheme 1
Scheme 2
proposed mechanism was supported by the experiment shown
in Scheme 3. Treatment of iodide 1a with excess phenyl-
Scheme 3
not surprising.7 A possible mechanism is shown in Scheme
2. Coordination of the pyrimidine ring N-atom with i-PrMgCl
leads to complex 5. The subsequent transfer of the â-hydride
of the i-Pr group furnished the reduction products 4a,b. This
magnesium chloride in THF yielded imidazole 2a along with
phenyl dihydropyrimidine 6 as the only byproduct. The lack
Table 1. Iodine-Magnesium Exchange with i-PrMgCl in THF
entry
substratea
additiveb
temp (°C)
conversion (%)c
time (min)
2 (%)d
3 (%)d
4 (%)d
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
none
none
none
NMM
TMEDA
7
-40
-20
0
66
98
180
30
5
90.5
73.3
68.1
69.0
83.7
98.7
93.5
97.1
85.0
74.5
74.0
92.5
99.8
85
71.9
89.0
97.3
96.7
86.5
66.0
90.4
98.2
6.5
20.0e
24.9
24.6
14.5
1.3
3.0
6.7
7.0
6.4
1.8
0
1.4
0.4
2.1
4.0
4.5
1.0
0
3
>99
>99
98
4
0
5
5
0
25
25
25
30
5
6
0
97
98
7
7f
0
5.1
8
8
9
0
>98
>98
>99
>99
98
2.5
9
0
12.9
21.5e
21.5
6.5
10
11
12
13
14
15
16
17
18
19
20
21
22
none
DMEg
TMEDA
7
0
25
25
25
25
60
30
180
240
240
180
30
180
240
0
0
0
98
80
0.2
9.5
1c (Ar ) 1,4-Ph)
none
none
TMEDA
7
-20
0
5.5h
9.9
6.0
0.7
1.0
6.0
12.0h
3.5
0
1c
>99
97
17.2
5.0
1c
0
1c
0
97
2.0
1c
8
9
0
97
2.3
1c
0
98
7.5
1d (Ar ) 1,3-Ph)
none
TMEDA
7
0
>99
98
22.0
6.1
1d
1d
0
0
98
1.8
a 1a,b prepared using a procedure in ref 3b; 1c,d prepared by Suzuki coupling of the corresponding phenyl diiodides. b 1.0 equiv of additive used.
c Excess i-PrMgCl added untill >97% conversion in some cases. d Ratio of 2:3:4 determined by HPLC based on their protonated products after quenching
the reaction mixture with water. e 1:1 mixture of two diastereomers for 3a and 3b. f 0.5 equiv of 7 used. g DME as solvent in place of THF. h 4 was oxidized
to 2 during isolation.
3142
Org. Lett., Vol. 8, No. 14, 2006

of â-hydrogen atoms on the phenyl ring is consistent with
the lack of reduction product observed.
Table 2. Iodine-Magnesium Exchange with i-PrMgCl in the
Presence of 7 Followed by Addition of Electrophiles
When the iodine-magnesium exchange of 1a with i-
PrMgCl was conducted at lower temperature (-40 °C), a
very sluggish exchange was observed. Although the two
byproducts 3a and 4a were detected at a lower level, the
exchange could not be driven to completion (Table 1, entry
1). On the other hand, as expected the same exchange of 1a
at higher temperature (0 °C) was complete in 5 min to
provide higher levels of 3a (20%) and 4a (7%) (entry 2).
The evidence of complexation between the pyrimidine ring
and the Grignard reagent led to the proposal that preventing
this type of association may significantly reduce the forma-
tion of these side products. Recently, we have demonstrated
that bis(N,N-dimethylaminoethyl) ether (7) is capable of
complexing Grigdard reagents to provide complexes with
reduced reactivity.8,9 We envisioned that the complexation
of the Grignard reagent with a ligand such as 7 would prevent
the pyrimidine ring from forming complex 5 with i-PrMgCl.
As a result, the pyrimidine ring would be less reactive toward
the attack by i-PrMgCl and the reduction pathway could be
eliminated.
We proceeded to evaluate N,N,N′,N′-tetramethylethylene-
diamine (TMEDA) as the suitable additive for our iodine-
magnesium exchange process, because TMEDA and ana-
logues have been found to strongly chelate organometallic
reagents, especially organolithiums.10 A detailed study as
summarized in Table 1 was conducted with different addi-
tives and substrates. When iodoimidazoles 1a,b were added
to a solution of i-PrMgCl in THF in the presence of 1.0 equiv
of TMEDA at 0 °C, a preferable temperature for large-scale
production, the exchange reaction proceeded rapidly, afford-
ing 2a,b after quenching with water. The reduction products
4a,b (<2%) were significantly reduced whereas a small
reduction of addition products 3a,b (∼10%) was observed
(entries 5 and 12). Apparently, an interaction between
TMEDA and the Grignard reagent partially avoids attack of
the organometallic species on the pyrimidine ring. Encour-
aged by this result, we next turned our attention to bis[2-
(N,N-dimethylamino)ethyl] ether (7), a tridentate ligand.8,11
Iodoimdazoles 1a,b underwent halogen-metal exchange
with 1.10 equiv of i-PrMgCl in THF at 0 °C in the presence
of 1.0 equiv of 7, reaching >98% conversion in 25 min.
Remarkably, in these two cases, no reduction products 4a,b
were observed while addition products 3a,b (<2%) were
a Reactions run at 0 °C in THF. b Isolated yield. c 53% yield without
adding 7. d 46% yield without adding 7. e NCS oxidation and morpholine
coupling after SO2 addition. f 49% yield without adding 7.
significantly reduced (entries 6 and 13). The suppression of
byproducts 3 and 4 may be attributable to the tridentate
interaction between 7 and i-PrMgCl. The same exchange of
1a with 0.5 equiv of 7 produced a higher degree of
byproducts 3a and 4a (entry 7). As a test for the importance
of the proposed tridentate complexation between i-PrMgCl
and 7, several other ligands were used for the same I/Mg
exchange. N-Methylmorpholine as an additive had no impact
on product distribution (entry 4), suggesting little interaction
between NMM and i-PrMgCl. Use of 1,2-dimethoxyethan
as solvent instead of THF in the absence of any additive
provided a similar product distribution as observed in THF
(entries 10 and 11). As we expected, I/Mg exchange of 1a
with i-PrMgCl in the presence of N,N,N′,N′,N′′-pentameth-
yldiethylenetriamine (8) as a tridentate ligand gave a very
similar result as 7 (entry 8). Interestingly, tris[2-(2-meth-
oxyethoxy)ethyl]amine (9) as a ligand showed a similar
effectiveness as that of TMEDA (Entry 9).
(7) (a) Talylor, H. M.; Jones, C. D.; Davenport, J. D.; Hirsch, K. S.;
Kress, T. J.; Weaver, D. J. Med. Chem. 1987, 30, 1359. (b) Weis, A. L.;
Vishkautsan, R. Chem. Lett. 1984, 1773. (c) Shadbolt, R. S.; Ulbricht, T.
L. V. J. Chem. Soc. 1968, 1203.
(8) (a) Wang, X.-j.; Zhang, L.; Sun, X.; Xu, Y.; Krishnamurthy, D.;
Senanayake, C. H. Org. Lett. 2005, 7, 5593. (b) Wang, X.-j.; Sun, X.; Zhang,
L.; Xu, Y.; Krishnamurthy, D.; Senanayake, C. H. Org. Lett. 2006, 8, 305.
(9) Diamines and polyethers have been used to complex Grignard
reagents, and the resulting complexes, where Mg coordination ranges from
4 to 6, have been characterized spectroscopically and by X-ray crystal-
lography, see: Uhm, H. L. In Handbook of Grignard Reagents; Silverman,
G. S., Rakita, P. E., Eds.; Marcel Dekker: New York, 1996; p 117.
(10) (a) Rutherford, J. L.; Hoffmann, D.; Collum, D. B. J. Am. Chem.
Soc. 2002, 124, 264. (b) Collum, D. B. Acc. Chem. Res. 1992, 25, 448.
(11) (a) Reich, H. J.; Goldenberg, W. S.; Sanders, A. W.; Jantzi, K. L.;
Tzschucke, C. C. J. Am. Chem. Soc. 2003, 125, 3509. (b) Lucht, B. L.;
Bernstein, M. P.; Remenar, J. F.; Collum, D. B. J. Am. Chem. Soc. 1996,
118, 10707.
Org. Lett., Vol. 8, No. 14, 2006
3143

To study the general scope of this new protocol, we
performed the exchange with less electron-deficient 5-(4′-
iodophenyl)pyrimidine (1c) and 5-(3′-iodophenyl)pyrimidine
(1d). Similar to 1a,b, the exchange of iodides 1c,d with
i-PrMgCl at 0 °C in the absence of any additive gave rise to
significant amounts of byproducts 3c,d and 4c,d (entries 15
and 20) while a sluggish reaction was observed at -20 °C
(entry 14). In the presence of 1.0 equiv of tridentate ligand
7, both 1c and 1d reacted with i-PrMgCl slowly at 0 °C,
reaching >97% conversion in 3-4 h without an additional
amount of i-PrMgCl being added providing predominantly
the desired 2c,d (>97%, entries 17 and 22). In both cases,
byproducts 3c,d and 4c,d were below 2%. The slow nature
of the exchange in the presence of 7 may suggest deactivation
of Grignard reagent by formation of complexes, which is
consistent with the suppression of the addition and reduction
of the pyrimidine ring by i-PrMgCl. TMEDA as an additive
for the same exchange was less effective in comparison with
7, but exhibited an obvious improvement in preventing the
formation of 3 and 4 (entries 16 and 21).
3-4 h, addition of the resulting Grignard reagents to an
aldehyde or DMF at 20 °C produced 11c,d and 12c,d in
excellent isolated yields. In contrast to the excellent result
described above, in the absence of 7, the same exchange of
1c and subsequent addition afforded 11c and 12c in <50%
yields (Table 2). Similarly, exchange of 1c,d in THF in the
presence of 7 at 0 °C for 3-4 h and addition of the resulting
Grignard reagents to SO2 followed by NCS and morpholine
furnished sulfonamide 12c,d in excellent yields.3,12
In conclusion, we have developed a new and mild protocol
for the selective iodine-magnesium exchange of iodoaro-
matics bearing the highly unstable pyrimidine ring, which
expands the current scope of organomagnesium reagents.
Furthermore, this concept of altering the reactivity of
Grignard reagent can be utilized in a number of other
instances and those are currently under investigation.
Supporting Information Available: A typical procedure
for iodine-magnesium exchange and spectroscopic data
1
including H NMR and 13C NMR spectra for compounds
1a-d, 2a-c, 3a-c, 4a,b, 6, 8a-d, and 9c-d. This material
is available free of charge via the Internet at http://pubs.acs.org.
Utilizing this newly discovered protocol for preparation
of arylmagnesium reagents bearing pyrimidine rings, the
subsequent addition of electrophiles was performed as
outlined in Table 2. Thus, after complete iodine-magnesium
exchange of 1c,d in THF in the presence of 7 at 0 °C for
OL061156S
(12) Frutos, R. P.; Johnson, M. Tetrahedron Lett. 2003, 44, 6509.
3144
Org. Lett., Vol. 8, No. 14, 2006