Hydroxymethylations of aryl halides by Pd-catalyzed cross-couplings with (benzoyloxy)methylzinc iodide - Scope and limitations of the reaction

Article abstract of DOI:10.1055/s-2008-1032084

Palladium-catalyzed cross-coupling reactions of (benzoyloxymethyl)zinc iodide with diverse (het)aryl halides leading to (benzoyloxymethyl)(het)arenes were studied to define the scope of this reaction. It has been found that this reaction is only applicable for electron-deficient aryl halides and the most efficient it is for 2-halopyridines and 4-halopyrimidines. Deprotection of the intermediates gives (hydroxymethyl)pyridines and -pyrimidines in high yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032084

LETTER
543
Hydroxymethylations of Aryl Halides by Pd-Catalyzed Cross-Couplings with
(Benzoyloxy)methylzinc Iodide – Scope and Limitations of the Reaction
C
ross-Coupling
b
H
ydroxyme
y
thylation něk Hasník, Peter Šilhár, Michal Hocek*
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead & IOCB Research Center,
Flemingovo nám. 2, 16610 Prague 6, Czech Republic
Fax +420(2)20183559; E-mail: hocek@uochb.cas.cz
Received 11 December 2007
BzOCH2ZnI (3 equiv)
Abstract: Palladium-catalyzed cross-coupling reactions of (ben-
zoyloxymethyl)zinc iodide with diverse (het)aryl halides leading to
(benzoyloxymethyl)(het)arenes were studied to define the scope of
this reaction. It has been found that this reaction is only applicable
for electron-deficient aryl halides and the most efficient it is for 2-
halopyridines and 4-halopyrimidines. Deprotection of the interme-
diates gives (hydroxymethyl)pyridines and -pyrimidines in high
yields.
1
ArX
Ar
OBz
3a–g
Pd(PPh3)4 (5 mol%)
THF, r.t., 6–8 h
2a–n
MeONa MeOH
r.t., 12 h
Ar
OH
4a–g
Key words: cross-coupling, organozinc reagents, pyridines, pyrim-
idines, palladium, hydroxymethylations
Scheme 1 Cross-coupling reaction
tection either with ammonia or NaOMe. Though we have
further used this reaction for regioselective synthesis7,9 of
either 2- or 6-(hydroxymethyl)purine bases and nucleo-
sides and it was used by us9 and others10 for preparation of
other hydroxymethylated nucleosides, the scope and lim-
itations of the method remained to be explored and this
communication reports on these results.
Hydroxymethyl groups attached to an aromatic or het-
eroaromatic ring is a very frequent structural motif in
many natural and/or bioactive molecules. Introduction of
the hydroxymethyl function to the aromatic ring could be
achieved in several ways: (i) direct electrophilic hy-
droxymethylations,1 (ii) electrophilic formylations2 fol-
lowed by reduction,3 (iii) generation of arylmetal species
and their reactions with formaldehyde or its equivalents,4
(iv) metalation and oxidation of methylaromatic deriva-
tives.5 None of them is generally applicable since the elec-
trophilic substitution is efficient only for electron-rich
aromatics and may lead to regioisomers, generation of or-
ganometallics may not tolerate functional groups and also
may form regioisomers due to migration of the metal (es-
pecially in the case of aryllithium species) and also the re-
dox reactions are not always efficient, selective, and
compatible with other functional groups. So far, no gener-
al direct nucleophilic hydroxymethylation of aryl halides
has been developed.
At first we have tested the reactivity of a set of 15 diverse
aryl halides 2a–n with (benzoyloxymethyl)zinc iodide 1
under standard conditions used for hydroxymathylation of
purines. The reactions were performed at ambient temper-
ature using three equivalents of the organozinc 1 and
Pd(PPh3)4 in THF (Scheme1). In general, only some elec-
tron-deficient aryl halides 2a–g were good substrates for
this reaction giving the desired (benzoyloxymethyl)arenes
3a–g (Table1), while electron-rich aryl bromides or io-
dides 2h,j,m,n, as well as 4-iodobenzonitrile (2i), 3-io-
dopyridine (2k) and 3-bromoquinoline (2l) were totally
unreactive (Figure1). The best reactivity was observed in
2-chloroazine derivatives 2d–f. Surprisingly, aryl bro-
mides and iodides were less reactive than aryl chlorides.
In the case of 2-iodo-5-bromopyrimidine (2g) the reaction
occurred exclusively in position 2 to give 2-(benzoy-
loxymethyl)-5-bromopyrimidine (3g) in quantitative
yield. In order to evaluate the influence of ligand, we have
tried the reaction of poorly reactive 2-iodopyridine (2bb),
as well as unreactive 2-bromonaphthalene (2j) with orga-
nozinc 1 in the presence of Pd2dba3 in combination with
Buchwald-type ligands (2-biphenyl)di-tert-butylphos-
phine (bpdbp),11 (2-biphenyl)dicyclohexylphosphine (bd-
Cyp),12 or with tri-tert-butylphosphonium tetra-
fluoroborate13 (in our previous study14 of cross-coupling
reactions of 6-halopurines with the Reformatsky reagent,
we have observed a strong increase in reactivity using this
type of ligands). While the reaction of 2-iodopyridine
(2bb) was strongly influenced by the ligand (yields when
Recently, we have developed an efficient hydroxymeth-
ylation of halopurines by the Pd-catalyzed cross-coupling
reactions with (acyloxymethyl)zinc iodides.6,7 This type
of reagents was developed by Knochel8 and used for trans-
metalation to cuprate and conjugate additions or Ullmann
coupling with vinyl halides. Our hydroxymethylation of
purines was the first example of their use in a Pd-cata-
lyzed cross-coupling. Three acyl protecting groups have
been tested6 to show that the acetyl group is too labile,
pivaloyl group is too stable for final deprotection, while
the benzoyl group is just perfectly stable enough for effi-
cient cross-coupling and labile enough for efficient depro-
SYNLETT 2008, No. 4, pp 0543–0546
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.02.2008
DOI: 10.1055/s-2008-1032084; Art ID: G40507ST
© Georg Thieme Verlag Stuttgart · New York

544
Z. Hasník et al.
LETTER
OBz
Table 1 Cross-Coupling Reaction
BzOCH2ZnI
(1.5 or 4 equiv)
1
Cl
Cl
N
Entry ArX
Coupling
(yield, %)
Deprotectiona
(yield, %)
+
N
N
N
Pd(PPh3)4
Cl THF, r.t., 6–8 h
OBz
OBz
X
N
X
N
X
I
6a,b
7a,b
1
2
3
4
2a
3a (69)
3b (76)
4a (95)
4b (73)
5a X = H
5b X = Cl
NO2
MeONa, MeOH
r.t., 12 h
2ba
2bb
2c
OH
Cl
N
N
Br
I
N
+
N
X
N
X
3b (17)
OH
OH
3b (72)b
unreactive
X
N
X
N
5c X = Cl
5d X = Br
8a,b
9a,b
Br
3c (55)
3d (96)
3e (95)
3f (68)
3g (96)
4c (81)
4d (96)
4e (97)
4f (72)
4g (75)
Scheme 2 Cross-coupling reaction of compounds 5a,b with subse-
N⋅HCl
quent deprotection
N
N
5
6
7
8
2d
2e
2f
Table 2 Cross-Coupling Reaction of Compounds 5a,b with Subse-
Cl
quent Deprotection
Entry
Starting com- 1 (equiv) Product
Deprotectionc
(yield, %)
N
N
Cl
pound
(yield, %)
1
2
3
5a
1.5
4a
6a (43)
7a (35)
8a (72)
N
Cl
Br
5a
5a
6a (37)
7a (30)
N
2g
I
N
4b
6a (38)
7a (54)
9a (76)
8b (35)
a 1 M NaOMe in MeOH (0.1 equiv).
b Catalyst: 2% Pd2dba3, 8% (2-biphenyl)dicyclohexylphosphine.
4
5
5b
5b
1.5
4a
6b (69)
6b (72)
7b (21)
I
I
4b
6b (64)
7b (24)
9b (74)
CN
6
5b
2h
2i
Br
Br
I
a 10% Pd(PPh3)4.
b 5% + 5% Pd(PPh3)4.
c For 6a and 7a,b: 1 M NaOMe in MeOH (0.1 equiv), 0 °C; for 6b: 1
M NaOMe in MeOH (0.1 equiv), r.t.
N
2k
2j
2l
Br
Further we were interested in the hydroxymethylation of
di- and trihalopyridines and -pyrimidines 5a–d. In our
previous study on dihalopurines, we have found7 useful
regioselectivity of the hydroxymethylations. While the
4,6-dichloro- and 2,4,6-trichloropyrimidine (5a,b) were
good substrates for the reaction with organozinc 1, 2,6-
dichloro- and 2,6-dibromopyridine (5c,d) were totally un-
reactive. Reaction of 4,6-dichloropyrimidine 5a with 1.5
equivalents of 1 was poorly regioselective giving the
mono- and disubstituted products 6a and 7a in 43% and
35% yields, respectively. The use of excess (4 equiv) of 1
with 10 mol% of Pd(PPh3)4 gave almost the same results
and only small increase in the yield of the disubstituted
derivative 7a (54%) was observed when the second por-
tion of the catalyst was added after six hours. On the other
hand, reaction of 2,4,6-trichloropyrimidine (5b) with 1.5
equivalents of 1 gave only monosubstituted product 6b
(69%) accompanied by unreacted starting compound. Re-
N
N
H
2m
Br
S
2n
Figure 1 List of unreactive aryl halides
using t-Bu3P⋅HBF4: 32%, bpdbp: 41%, and bdCyp: 72%),
2-bromonaphthalene was entirely unreactive irrespective
of the ligand used even when increasing the reaction tem-
perature up to 50 °C.
All the resulting (benzoyloxymethyl)arenes 3a–g were
successfully deprotected by cleaving the ester groups us-
ing NaOMe in methanol at room temperature giving the
desired benzylic alcohols 4a–g in high yields (Scheme1;
Table1, last column).
Synlett 2008, No. 4, 543–546 © Thieme Stuttgart · New York

LETTER
Cross-Coupling Hydroxymethylation
545
(m, 1 H), 8.13 (m, 2 H). 13C NMR (CDCl3): δ = 64.69, 116.66,
128.70, 128.72, 129.89, 133.89, 160.56, 163.43, 165.57, 169.68.
MS (EI): m/z (%) = 105 (100), 77 (50), 51 (30). HRMS (EI): m/z
calcd for C12H8N2O2Cl2: 281.9962; found: 281.9953. IR (CCl4):
2942, 1737, 1561, 1535, 1264, 1109 cm–1. Anal. Calcd (%) for
C12H8N2O2Cl2 (283.1): C, 50.91; H, 2.72; N, 9.89. Found: C, 50.63;
H, 2.72; N, 9.89.
action of 5b with 4 equivalents of 1 gave still preferential-
ly monosubstituted product 6b (72%) and only small
amount of the disubstituted compound 7b (21–24%).
Also the mono- and di(benzoyloxymethyl)pyrimidines 6
and 7 were deprotected to the desired hydroxymethylpyri-
midines using NaOMe in methanol. The deprotection on
pyrimidines 6a and 7a,b proceeded at 0 °C to avoid nu-
cleophilic substitutions on chloro substituents in a basic
media (Scheme2, Table2).
1
Compound 7b: yield 24% as yellowish crystals, mp 53–55 °C. H
NMR (CDCl3): δ = 5.44 (d, 4 H), 7.46 (m, 4 H), 7.46 (t, 1 H), 7.60
(m, 2 H), 8.04 (m, 4 H). 13C NMR (CDCl3): δ = 65.05, 112.61,
128.60, 128.96, 129.72, 133.62, 165.59, 169.28. MS (EI): m/z
(%) = 105 (100), 77 (55), 41 (25). HRMS (EI): m/z calcd for
C20H15N2O4Cl: 382.0720; found: 382.0724.
In conclusion, we have shown that the (benzoyloxy)meth-
ylzinc iodide is a suitable reagent for cross-coupling hy-
droxymethylation of certain aryl halides. However, the
scope of the reaction is quite narrow. The reaction pro-
ceeds only in electron-deficient aryl halides and the most
efficient it is for hydroxymethylation of 2-haloazines.
General Procedure for Deprotection
A 1 M methanolic NaOMe (50 µL, 0.05 mmol) was added to a so-
lution of a benzoylated compounds 3a–g, 6a,b, and 7a,b (0.25
mmol) in MeOH (15 mL) and the mixture was stirred at ambient
temperature. After complete deprotection the solvent was evaporat-
ed and the residue was chromatographed (CHCl3–MeOH).
Compound 4d: yield 96% as yellow oil. 1H NMR (CDCl3): δ = 3.64
(s, 1 H), 4.83 (s, 2 H), 8.47–8.53 (m), 8.64 (s, 1 H). 13C NMR
(CDCl3): δ = 62.77, 142.95, 143.43, 143.45, 154.95. MS (EI): m/z
(%) = 109 (20), 80 (20), 31 (90).
Compound 4g: yield 75% as white crystals, mp 93–94 °C. 1H NMR
(CDCl3): δ = 3.36 (s, 1 H), 4.81 (s, 2 H), 8.79 (s, 2 H). 13C NMR
(CDCl3): δ = 64.23, 118.46, 157.65, 166.60. MS (EI): m/z (%) = 187
(35), 158 (50), 52 (45). Anal. Calcd (%) for C5H5BrN2O (189.0): C,
31.77; H, 2.67; N, 14.82. Found: C, 31.78; H, 2.64; N, 14.39.
General Procedure for Cross-Couplings of 1 with Aryl Halides
A solution of (benzoyloxymethyl)zinc iodide (1, 3 mmol) in THF
was added at r.t. to a solution of an aryl halide (2a–n, 5a–d, 1
mmol), Pd(PPh3)4 (58 mg) in THF (2 mL) and stirred at r.t. for 6–8
h. The reaction was quenched with 1 M NaH2PO4 (30 mL) and ex-
tracted with CHCl3 (3 × 25 mL). Collected organic phases were
dried over MgSO4, filtered, and the solvent was evaporated. The
crude oily product was purified by chromatography.
1
Compound 3d: yield 96%, yellowish crystals, mp 45.5–47 °C. H
NMR (CDCl3): δ = 5.53 (s, 2 H), 7.46 (m, 2 H), 7.59 (m, 1 H), 8.11
(m, 2 H), 8.56–8.61 (m, 2 H), 8.79 (s, 1 H). 13C NMR (CDCl3): δ =
65.09, 128.48, 129.38, 129.79, 133.39, 143.66, 144.07, 144.13,
151.59, 166.03. MS (EI): m/z (%) = 105 (100), 77 (65), 51 (30).
HRMS (EI): m/z calcd for C12H10N2O2: 214.0742; found: 214.0748.
Compound 8a: yield 72% as yellow oil. 1H NMR (CDCl3): δ = 3.07
(s, 1 H), 4.78 (s, 2 H), 7.47 (s, 1 H), 8.93 (s, 1 H). 13C NMR (CDCl3):
δ = 63.60, 118.10, 158.20, 161.77, 170.43. MS (EI): m/z (%) = 143
(100), 115 (40), 52 (40). HRMS (EI): m/z calcd for C5H5N2OCl:
144.0090; found: 144.0087.
Compound 9a: yield 76% as yellow oil. 1H NMR (CDCl3): δ = 4.55
(d, 4 H), 5.67 (t, 2 H), 7.70 (s, 1 H), 8.91 (s, 1 H). 13C NMR (CDCl3):
δ = 63.30, 113.03, 156.65, 171.01. MS (EI): m/z (%) = 139 (100),
111 (100), 52 (70). HRMS (EI): m/z calcd for C6H8N2O2: 140.0585;
found: 140.0582.
1
Compound 3f: yield 68% as yellowish crystals, mp 76–77 °C. H
NMR (CDCl3): δ = 5.70 (s, 2 H), 7.47 (m, 2 H), 7.60 (m, 1 H), 7.76–
7.84 (m, 2 H), 8.08–8.17 (m, 3 H), 9.05 (s, 1 H). 13C NMR (CDCl3):
δ = 66.03, 128.54, 129.30, 129.37, 129.45, 129.89, 130.16, 130.45,
133.46, 141.84, 142.23, 144.22, 151.01, 166.16. MS (EI): m/z
(%) = 265 (25), 181 (30), 91 (40). HRMS (EI): m/z calcd for
C16H13N2O2: 265.0977; found: 265.0984. IR (CCl4): 3071, 1730,
1603, 1494, 1452, 1264, 1108 cm–1.
1
Compound 8b: yield 35% as white solid, mp 94–96 °C. H NMR
(CDCl3): δ = 2.79 (t, 1 H), 4.77 (dd, 2 H), 7.47 (t, 1 H). 13C NMR
(CDCl3): δ = 63.65, 116.42, 160.17, 163.10, 173.77. MS (EI): m/z
(%) = 177 (100), 148 (45), 113 (55).
Compound 3g: yield 96% as yellow oil. 1H NMR (CDCl3): δ = 5.52
(s, 2 H), 7.46 (m, 2 H), 7.58 (m, 1 H), 8.13 (m, 2 H), 8.77 (s, 2 H).
13C NMR (CDCl3): δ = 65.87, 119.04, 128.42, 129.62, 129.91,
133.25, 157.95, 163.43, 166.22. MS (EI): m/z (%) = 105 (100), 77
(65), 51 (40). HRMS (EI): m/z calcd for C12H9N2O2Br: 291.9847;
found: 291.9842.
Compound 9b: yield 74% as white solid, mp 165–172 °C. 1H NMR
(DMSO-d6): δ = 4.54 (d, 4 H), 5.79 (t, 2 H), 7.68 (s, 1 H). 13C NMR
(DMSO-d6): δ = 62.94, 112.16, 158.49, 175.38. MS (EI): m/z (%) =
173 (60), 145 (50), 32 (95).
Compound 6a: yield 43% as beige crystals, mp 79–80 °C. 1H NMR
(CDCl3): δ = 5.46 (d, 2 H, J = 0.8, CH2), 7.47 (dt, 1 H), 7.52 (m, 2
H), 7.65 (m, 1 H), 8.14 (m, 2 H), 8.98 (d, 1 H). 13C NMR (CDCl3):
δ = 65.07, 118.42, 128.67, 128.95, 129.86, 133.75, 158.63, 162.16,
165.73, 166.83. MS (EI): m/z (%) = 105 (100), 77 (50), 51 (30).
HRMS (EI): m/z calcd for C12H9N2O2Cl: 248.0352; found:
248.0360. IR (CCl4): 3064, 1734, 1569, 1540, 1267, 1112 cm–1.
Acknowledgment
This work is a part of the research project Z4 055 0506. It was sup-
ported by the ‘Centre for New Antivirals and Antineoplastics’
(1M0508), by the Programme for Targeted Research
(1QS400550501) and by Gilead Sciences, Inc.
Compound 7a: yield 54% as yellowish crystals, mp 109–113 °C. 1H
NMR (CDCl3): δ = 5.48 (d, 4 H), 7.42 (m, 4 H), 7.55 (dt, 1 H), 7.60
(m, 2 H), 8.07 (m, 4 H, 2 × H-o-Ph), 9.17 (s, 1 H). 13C NMR
(CDCl3): δ = 65.51, 114.24, 128.56, 129.17, 129.72, 133.50,
158.27, 165.75, 165.78. MS (EI): m/z (%) = 304 (10), 105 (100), 77
(55), 51 (15). HRMS (EI): m/z calcd for C20H16N2O4: 348.1110;
found: 348.1122. IR (CCl4): 2945, 1734, 1595, 1272, 1111 cm–1.
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Synlett 2008, No. 4, 543–546 © Thieme Stuttgart · New York

546
Z. Hasník et al.
LETTER
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Synlett 2008, No. 4, 543–546 © Thieme Stuttgart · New York

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