Microwave promoted reaction of purin-6-yl magnesium halides with aldehydes in dichloromethane at 100u202f°C

Article abstract of DOI:10.1016/j.tetlet.2018.04.014

Treatment of a dichloromethane solution of 9-benzyl or 9-phenyl 6-iodopurine with ethereal ethylmagnesium bromide at ambient temperature gives the corresponding purin-6-yl magnesium halides. Addition of an aldehyde followed by heating at 100 °C in a microwave reactor yielded the corresponding carbinols in 52–81% yield.

Full text of DOI:10.1016/j.tetlet.2018.04.014

Accepted Manuscript
Microwave promoted reaction of purin-6-yl magnesium halides with aldehydes
in dichloromethane at 100 °C
Malcolm R. Gordon, Stephen D. Lindell
PII:
S0040-4039(18)30457-X
https://doi.org/10.1016/j.tetlet.2018.04.014
TETL 49877
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
27 February 2018
27 March 2018
9 April 2018
Please cite this article as: Gordon, M.R., Lindell, S.D., Microwave promoted reaction of purin-6-yl magnesium
halides with aldehydes in dichloromethane at 100 °C, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/
j.tetlet.2018.04.014
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Tetrahedron Letters
Microwave promoted reaction of purin-6-yl magnesium halides with aldehydes in
dichloromethane at 100 °C
a
a,
Malcolm R. Gordon and Stephen D. Lindell 
a
Bayer AG, Crop Science Division, Industriepark Höchst, 65926 Frankfurt am Main, Germany
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Treatment of a dichloromethane solution of 9-benzyl or 9-phenyl 6-iodopurine with ethereal
ethylmagnesium bromide at ambient temperature gives the corresponding purin-6-yl magnesium
halides. Addition of an aldehyde followed by heating at 100 °C in a microwave reactor yielded
the corresponding carbinols in 52-81% yield.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
purin-6-yl magnesium halide
microwave
dichloromethane
nucleobase
Grignard
Introduction
Purines play an essential role in many enzymatic reactions and
in the biological regulation of all living organisms. They are
integral constituents of DNA and RNA, and are involved in
energy regulation as adenylates, signal transduction (GTP and
cAMP), metabolism (NAD/NADH) and neurotransmission
1
(
purinergic receptors). Purine derivatives containing C-
substituents at the C-6 position show a variety of biological
2 2
Scheme 1. Metal halogen exchange of 6-iodopurines in CH Cl
properties of interest within the agrochemical and pharmaceutical
2
industries. For example, certain 6-hydroxymethyl- and 6-
aminomethyl-purine nucleosides show interesting levels of
3
this improved method required an excess of electrophile (3
equiv.), as do all other reported methods describing the reaction
of purin-6-yl anions with aldehydes. The yield of carbinol 3a
decreased from 79% to 50% and of 4a from 75% to 47% when
the amount of benzaldehyde was reduced from 3 to 1.1
equivalents. The other major products formed in ca. equimolar
amounts to 3a and 4a were the unsubstituted purines 5 and 6
cytostatic and/or anti-hepatitis
C
viral activity. These
compounds were synthesised from 6-iodo-9-substituted purines
4,6
via a Negishi cross-coupling reaction with an acyloxymethyzinc
3
iodide. Alternatively, 6-iodo purines can be transformed into 6-
4
5
6
lithiated, 6-zincated or 6-magnesiated purines which can then
be reacted with various electrophiles to yield purines containing
a C-6 carbon substituent. However, this approach is hampered by
the tendency of these organometallic intermediates to undergo
(Scheme 1). Repeating the reaction with the phenyl purine 2, but
4
quenching after 60 min with D O yielded the 6-deutero derivative
2
isomerisation to C-8 anions or by low yielding reactions, for
of 6 in high yield (98%), indicating that the 6-magnesioanion had
been formed in near quantitative yield. A second repeat
6
example with enolizable aldehydes.
2 2
conducted in CD Cl followed by quenching with water after 16
Results and Discussion
h gave a good yield of compound 6 (70%) but showed no
deuterium (or chlorine) incorporation, indicating that the anion
was stable and that dichloromethane was not participating in the
reaction. Finally the reaction was repeated again, this time with
addition of benzaldehyde 15 min after anion formation, followed
We recently reported a method for the generation of stable 6-
magnesiopurines by metal halogen exchange of 6-iodopurines 1
7
or 2 with EtMgBr in CH
Cl
2 2
at ambient temperature. These
anions reacted with various aromatic and aliphatic aldehydes to
give corresponding 6-carbinols in 55-80% yield. However, even
by quenching with D O after 16 h. Work-up and
2
chromatographic purification yielded compound 4a (41%) and
—
——

Stephen Lindell. e-mail: stephen.lindell@bayer.com

2
Tetrahedron
compound 6 showing ca. 30% deuterium incorporation at the 6-
enolizable aliphatic aldehydes (Entries 4, 6, 10 and 12) (52-65%).
The stability of the purin-6-yl magnesium halides at 100°C in
position (38%). This result was surprising and indicated that the
purin-6-yl magnesium halide was present even after 16 h in the
presence of benzaldehyde, apparently in a form able to react with
2 2
CH Cl seems quite remarkable when compared to the extensive
decomposition seen even at rt in THF, where only low yields of
7
D
2
O but not with an aldehyde. In an attempt to disrupt postulated
impure carbinols are obtained (<15%).
organometallic aggregates and thereby increase the reactivity of
the 6-magnesio anion, a number of different additives were tested
including TMEDA, Et N, LiCl, MgBr and TMSCl. However,
3 2
with the exception of TMSCl (3 equiv.) which increased the yield
of 4a from 47% to 64%, no significant effects were observed.
Standard reaction conditions were as follows: A 3M solution
of EtMgBr (1.2 mmol) in diethyl ether was added over 30 sec. to
a 0.1M solution of the 6-iodopurine 1 or 2 (1 mmol) in dry
CH Cl at ambient temperature and under an inert gas
2 2
atmosphere. The resulting mixture was stirred at r.t. for 15 min.
and then neat aldehyde (1.1 mmol) was added to the mixture over
3
0 sec. The reaction mixture was then heated for 1 h at 100 °C in
8
a Biotage Initiator microwave reactor. Following work-up and
purification by column chromatography the carbinols 3a-f and
9
4a-f were isolated in 52-81% yield (Table 1).
Scheme 3. Synthesis of keto and tertiary carbinol derivatives
2 2
Scheme 2. Metal halogen exchange of 6-iodopurines in CH Cl
followed by anion quenching with aldehydes at 100 °C
The product yields obtained in the current work are
comparable to those obtained in our previous room temperature
studies. However, the current method has the advantage of a
7
Table 1. Reaction of purin-6-yl magnesium halides with aldehydes
in CH Cl at 100°C in a microwave reactor
2
2
much shorter reaction time (1 h vs. 16 h) and the use of only a
single equivalent of electrophile as opposed to the three
equivalents previously required. Attempts to extend the present
R1
R2
Entry
Compd
No
Isolated
yield
7
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
Bn
Bn
Bn
Bn
Bn
Bn
Ph
Ph
Ph
Ph
Ph
Ph
Ph
78%
81%
55%
63%
74%
58%
75%
75%
52%
65%
81%
52%
or previously reported methodology to other electrophiles such
as acid chlorides, acid anhydrides, nitriles or ketones failed or
gave only low yields. However, the keto and tertiary alcohol
products expected from these reactions can be readily synthesised
starting from the carbinols 3 and 4. For example, oxidation of 4a
with pyridinium chlorochromate yielded ketone 7 in 87% yield,
which reacted with ethylmagnesium bromide to give the tertiary
4-CF
3
C
6
H
4
2 6 3
3,4-(OCH O)C H
i-Pr
c-Pr
n-Pr
Ph
9
4a
4b
4c
4d
4e
4f
alcohol 8 in 86% yield (Scheme 3).
4-CF
3,4-(OCH
i-Pr
3 6 4
C H
2
O)C
6
H
3
Acknowledgments
10
11
12
We thank the European Commission for a Marie Curie
Fellowship for M. Gordon (FP7-PEOPLE-2012-ITN, Project:
ECHONET “Expanding Capability in Heterocyclic Organic
Synthesis,” No. 316379)
c-Pr
n-Pr
Our next attempt to increase the reactivity of the purin-6-yl
magnesium halides was by increasing the reaction temperature.
The metal halogen exchange was performed on iodopurines 1 or
References and notes
2
with EtMgBr in CH
Cl
2 2
at ambient temperature as before, then
1.
2.
a) Rosemeyer, H.; Chem. Biodiversity, 2004, 1, 361-401. b)
Burnstock, G.; Verkhratsky, A. WIREs Membr. Transp. Signal.,
after 15 min 1.2 equivalents of benzaldehyde were added and
immediately thereafter heating was started. Due to the low
boiling point of CH Cl the reactions were conducted in a sealed
2 2
2
012, 1, 116–125. doi: 10.1002/wmts.14. c) Zhao, H.; French, J.
B.; Fang, Y.; Benkovic, S. J. Chem. Commun., 2013, 49, 4444-
452
4
vessel in a microwave reactor. Pleasingly these experiments
showed a significant temperature effect and by increasing the
temperature to 100 °C for 60 min immediately after addition of
benzaldehyde, the yields of carbinols 3a and 4a could be
increased to 77% and 75%, respectively. The reaction was
general for a variety of aryl and alkyl aldehydes to give the
corresponding carbinols in 52-81% yield as shown in Scheme 2
and Table 1. The best yields were obtained with the more
electron deficient aromatic aldehydes (Entries 1, 2, 7 and 8) or
with cyclopropyl carboxaldehyde (Entries 5 and 11) (74-81%).
Lower but still very acceptable yields were obtained with
electron rich aromatic aldehydes (Entries 3 and 9) or with
a) Brændvang, M.; Gundersen, L.-L. Bioorg. Med. Chem., 2007,
15, 7144-7165. b) Kuchař, M.; Hocek, M.; Pohl, R.; Votruba, I.;
Shih, I-H.; Mabery, E.; Mackman, R. Bioorg. Med. Chem., 2008,
1
6, 1400-1424. c) Kuchař, M.; Pohl, R.; Klepetářová, B.; Hocek,
M. Tetrahedron, 2008, 64, 10355-10364.
3
.
Šilhár, P.; Pohl, R.; Votruba, I.; Hocek, M. Org. Lett., 2004, 6,
3
225-3228. b) Šilhár, P.; Hocek, M.; Pohl, R.; Votruba, I.; Shih, I.;
Mabery, E.; Mackman, R. Bioorg. Med. Chem., 2008, 16, 2329-
366.
2
4
5
.
.
Leonard, N. J.; Bryant, J. D. J. Org. Chem., 1979, 44, 4612-4616.
Prasad, A. S. B.; Stevenson, T. M.; Citineni, J. R.; Nyzam, V.;
Knochel, P. Tetrahedron, 1997, 53, 723-754.
6
.
Tobrman, T.; Dvořák, D. Org. Lett., 2003, 5, 4289-4291.

7
8
.
.
Gordon, M. R.; Lindell, S. D.; Richards, D. Synlett, 2018, 28, 473-
76.
Biotage AB, Box 8, 751 03 Uppsala, Sweden. See
2 2
were stirred in CH Cl (10 mL) at rt until TLC showed full
conversion. The mixture was filtered through Celite and
4
chromatographed to give pure phenyl(9-phenyl-9H-purin-6-
1
13
http://www.biotage.com/product-page/biotage-initiator and
http://www.biotage.com/product-page/microwave-reaction-vials
General experimental procedure for the microwave promoted
reaction of purin-6-yl magnesium halides with aldehydes in
dichloromethane: Dry dichloromethane (10 mL) was added to the
yl)methanone (7) (314 mg, 1.1 mmol, 87%): H and C NMR
spectra were identical to those reported previously by Miyashita
1
0
9
.
and co-workers.
1-Phenyl-1-(9-phenyl-9H-purin-6-yl)propan-1-ol
solution of EtMgBr (3M in Et O, 0.4 mL, 1.2 mmol) was added
over 30 sec to a stirred solution of phenyl(9-phenyl-9H-purin-6-
yl)methanone (7) (300 mg, 1.0 mmol) in dry CH Cl (10 mL) at rt
under an atmosphere of dry argon. After 4 h, a sat. aq. solution of
NaHCO (15 mL) was added. The organic phase was separated
and the aqueous phase extracted with dichloromethane (3 x 20
mL). The combined organic phases were dried over MgSO
(8):
A
2
7
iodopurine 1 or 2 (1.0 mmol) under an inert atmosphere of dry
argon and the mixture was stirred at r.t. until the purine was
2
2
completely dissolved. A solution of EtMgBr (3M in Et
2
O, 0.4 mL,
1
.2 mmol) was then added to the solution over a period of 30 sec.
3
The resulting mixture was stirred at r.t. for 15 min., then neat
aldehyde (1.1 mmol) was added to the mixture over 30 sec and the
reaction mixture was heated to 100 °C in a sealed thick-walled
microwave reaction vial using a Biotage Initiator microwave
4
,
filtered and concentrated in vacuo. Column chromatography
yielded pure 1-phenyl-1-(9-phenyl-9H-purin-6-yl)propan-1-ol (8)
8
1
reactor. The temperature was maintained at 100 °C for 60 minutes
as a colourless solid (285mg, 0.86mmol, 86%). H NMR (600
and then allowed to cool to r.t. before the reaction mixture was
3
MHz, CDCl ): δ 0.94 (t, J = 6 Hz, 3H), 2.68 (m, 1H), 2.91 (m,
quenched by the addition of 1M aqueous NH
diluted with sat. aq. NaHCO (15 mL). The organic phase was
separated and the aqueous phase extracted with dichloromethane
3 x 20 mL). The combined organic phases were dried over
MgSO , filtered and concentrated in vacuo at 40 °C. The crude
4
Cl (5 mL) and then
1H), 6.22 (bs, 1H), 7.19 (t, J = 6 Hz, 1H), 7.32 (t, J = 6 Hz, 2H),
7.48 (t, J = 6 Hz, 1H), 7.58 (t, J = 6 Hz, 2H), 7.66 (d, J = 6 Hz,
3
1
3
4H), 7.86 (d, J = 6 Hz, 2H), 8.32 (s, 1H), 8.98 (s, 1H) ppm.
C
(
NMR (150 MHz, CDCl3): δ 8.2, 33.1, 78.9, 123.7, 126.0, 127.0,
128.1, 128.7, 130.0, 130.7, 134.1, 142.8, 145.5, 151.7, 151.9,
4
product was purified by column chromatography to afford pure
163.9 ppm. (IR, solid): ʋ
1266, 1230, 910 cm-1. HRMS (ESI/QTOF) m/z: [MH]+ Calcd for
20 19 4
C H N O 331.1559; Found 331.1559.
m
3434, 3056, 2970, 1583, 1508, 1333,
carbinols 3a-f and 4a-f (see Table 1 for yields).
1
13
The H and C NMR spectra for compounds 3a-d were identical
6
to those reported previously by Tobrman and Dvořák a7nd for
10. Miyashita, A.; Suzuki, Y.; Iwamoto, K.; Higashino, T. Chem.
Pharm. Bull., 1998, 46, 390-399.
compounds 3e-f and 4a-f to those reported by Gordon et al.
Phenyl(9-phenyl-9H-purin-6-yl)methanone
(7):
Phenyl(9-
phenyl-9H-purin-6-yl)methanol (4a) (363 mg, 1.2 mmol),
pyridinium chlorochromate (517 mg, 2.4 mmol) and Celite (5g)

3
Graphical Abstract
Microwave promoted reaction of purin-6-yl magnesium Leave this area blank for abstract info.
halides with aldehydes in dichloromethane at 100 °C
Malcolm R. Gordon and Stephen D. Lindell*

Tetrahedron
4
Highlights
Generation of purin-6-yl magnesium halides in
dichloromethane
Microwave assisted reaction with aldehydes at 100
°C
Preparation of purin-6-yl carbinol and keto
derivatives