Efficient synthesis of 2H & 13C labeled benzaldehydes via regio-selective formylation

Article abstract of DOI:10.1016/j.tetlet.2014.06.053

Benzaldehydes are important building blocks in synthetic organic chemistry that have wide applications for the synthesis of natural products and pharmaceutical drugs. Herein we report a general synthetic methodology for the synthesis of highly functionalized ²H and ¹³C labeled benzaldehydes in transfer of isotopic purity >99% via regio-selective formylation. Regio-selective deprotonation of substituted benzene 1 with LDA/n-BuLi at -78 °C and treatment with DMF-d₇ or EtO- ¹³CHO led to the synthesis of 2-deutero-1,3-disubstituted benzaldehydes 2/4 in moderate to good yields. The synthetic methodology described represents a simple yet versatile route to functionalized formyl-deuterated, tritiated ¹³C and ¹⁴C labeled benzaldehydes.

Full text of DOI:10.1016/j.tetlet.2014.06.053

Accepted Manuscript
Efficient synthesis of 2H & 13C labeled benzaldehydes via Regio-selective for-
mylation
Sobhana B. Boga, Abdul B. Alhassan, David Hesk
PII:
S0040-4039(14)01044-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.06.053
TETL 44777
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
24 March 2014
12 June 2014
13 June 2014
Please cite this article as: Boga, S.B., Alhassan, A.B., Hesk, D., Efficient synthesis of 2H & 13C labeled benzaldehydes
via Regio-selective formylation, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.06.053
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Efficient Synthesis of 2H & 13C labeled benzaldehydes
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via Regio-selective formylation.
Sobhana B. Boga*, Abdul B. Alhassan, David Hesk

Tetrahedron Letters
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Efficient synthesis of 2H & 13C labeled benzaldehydes via Regio-selective formylation.
Sobhana B. Boga*, Abdul B. Alhassan, David Hesk
Department of Chemical Research, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ, 07065, USA. E-mail: sobhana.babu.boga@merck.com
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Benzaldehydes are important building blocks in synthetic organic chemistry that have wide
applications for the synthesis of natural products and pharmaceutical drugs. Herein we report a
general synthetic methodology for the synthesis of highly functionalized 2H and 13C labeled
benzaldehydes in transfer of isotopic purity >99% via regio-selective formylation. Regio-
o
Available online
selective deprotonation of substituted benzene 1 with LDA / n-BuLi at -78 C and treatment
with d7-DMF or EtO-13CHO led to the synthesis of 2-deutero-1,3-disubstituted benzaldehydes
2/3 in moderate to good yields. The synthetic methodology described represents a simple yet
versatile route to functionalized formyl-deuterated, tritiated 13C and 14C labelled benzaldehydes.
Keywords:
Deuterium, 13
C
Isotopic effect
Labeled benzaldehyde
Metabolic stability
2009 Elsevier Ltd. All rights reserved.
Regio-selective formylation
Scheme 1. Reagents and conditions: (a) LDA, d7-DMF, THF, _78
1. Introduction
oC, 1h b) n-BuLi, d7-DMF, THF, _78 oC, 1h.
Benzaldehydes are important building blocks in synthetic
organic chemistry that have wide applications for the synthesis of
natural products and pharmaceutical drugs. During the course of
drug development it is necessary to prepare radiolabelled and
stable isotope labelled analogs for metabolic and bioanalytical
studies. Drug metabolism often involves the breaking of a C-H
bond, therefore deuterium substitution at specific molecular
positions has the potential to improve metabolic stability and
show a differentiated PK profile due to the diffreneces in kH/kD
known as kinetic isotopic effect (KIE). 1-3
Table 1 Synthesis of 2H labeled benzaldehydes 2
No.
Reactant
Product
yield (%)conditions
1
58a
2
3
4
5
6
7
89 a
80 a
78 a
79 a
82 a
85 a
The reported methods to prepare formyl labelled
benzaldehydes with hydrogen and carbon isotopes typically
involve a muti-step approach or generate additional ortho
exchange.4-7 We became interested in developing methodology to
selectively introduce the labelled formyl group in a single step
from commercially available 2H and 13C starting materials, which
3
could then be potentially applied to the incorporation of H and
14C isotopes.
2. Results and discussion
The synthesis of highly functionalized deuterated
benzaldehydes in 100 % isotopic purity was carried out via regio-
selective deutero-formylation. Regio-selective deprotonation of
substituted benzenes 1 with LDA or n-BuLi at -78 oC and
treatment with d7-DMF led to the synthesis of 2-formyl deutero
substituted benzaldehydes 2 in moderate to good yieilds.8 The
synthetic methodology described represents a simple yet versatile
route to functionalized formyl-deuterated benzaldehydes (scheme
1, Table 1).

2
8
9
92 a
75 a
72 a
70 b
75 b
Table 2 Synthesis of 13C lableled benzaldehydes 4
No.
Reactant
Product
yield (%)conditions
1
84 a
80 a
75 a
75 b
70 b
2
3
4
5
10
11
12
Efficacy of this synthetic transformation and optimization of this
reaction (Table 1, entry 2) was challenged by different bases viz.,
n-BuLi, LDA, LiHMDS, NaHMDS, K-OtBu for deprotonation
and with different sources of deutero formylating agents
viz.,DMF-d7, DMF-d1, EtOCDO. Remarkably, it was observed
that usuing n-BuLi, LDA resulted in a significant acceleration of
the reaction with best yields (85-90%) while DMF-d7, DMF-d1
being the best source for deutero formylation.
Acknowledgments
We thank Drs. Jeffrey Hale, Joseph Kozlowski and Joseph Duffy
for their strong support at Merck Research Labs (MRL). We
thank the MRL Structural Chemistry group for providing NMR
and Mass Spectral data.
As an application to this synthetic methodology, we have also
exploited this reaction for the preparation of 13C labelled
benzaldeydes (Scheme 2) in good yields with >99% isotopic
purity using EtO13CHO as a source. Usage of n-BuLi as a base
underwent metal-halogen exchange that resulted in the isolation
of novel fluorinated or Bromine substituted deutero- & 13C-
References and notes
1. Shao, L.; Hewitt, M.C. Drug News & Perspectives. 2010, 23,
398-404.
2. Tung, R Innovations in Pharmaceutical Technology. 2010), 32
24-26, 28.
3. Halliday, D.; Lockhart, I.M.; Progress in medicinal chemistry,
1978, 15, 1-86
4. Bennett, D.J, Kirby G.W. and Moss V.A., J. Chem. Soc. (C),
1970, 2049.
formyl benzaldehydes.
d7-DMF & 13C carbonyl labeled
DMF/Ethylformate served to be an excellent source of deuterium
and 13C for the synthesis of >99% isotopically enriched
substituted benzaldehydes (Scheme 2, Table 2).
5. Chappelle M.R, and Hawes C.R., Journal of Labelled compounds
and Radiopharmaceuticals. 2010, 53, 745-751.
6. Voges R, Heys, J.R. and Moenius T,. Preparation of Compounds
Labelled with Tritium and Carbon-14, Wiley, 2009.
7. Elmore, C.S. Journal of Labelled Compounds and
Radiopharmaceuticals. 2011, 54, 59-64.
8. General procedure for the Synthesis of 2H or 13C labeled
benzaldehydes 2/4: To Reactant 1 or 3 (1g, 8.76 mmol) in THF
(50 ml), was added LDA (condition A) or n-BuLi (condition
B)(4.82 ml, 9.64 mmol) at -78 °C slowly, after 30 min, added
EtO-13CHO/ DMF-13CHO (0.736 ml, 9.64 mmol) and left for
stirring at -78 °C for 30 min. Quenched with a few drops of dil .
Scheme 2. Reagents and conditions: (a) LDA, EtO-13CHO/ DMF-
_
o
13CHO, THF, 78 C, 1h (b) n-BuLi, EtO-13CHO/ DMF-13CHO,
H2SO4 (aq) and sat. NH Cl (aq 50 mL)), extracted with
THF, _78 oC, 1h
4
Et2O(3X50 mL), dried, purified by column chromatography on
silica gel eluting with a solution of EtOAc/hexane(1:9) to give
products 2 or 4 (0.860 g, 69 % yield). Representative data for 2b.
1H NMR (600 mHz, CDCl3) δ: 7.56 (1H, m), 6.97(2H, t, J 10
Hz).13C NMR (150 MHz, CDCl3) δ: 184.2 (1C, dt, J 28.5 Hz, 4.3
Hz), 163.1 (1C, dd, J 262.9 Hz, 5.7 Hz), 136.2 (1C, t, J 11.6 Hz),
114.1 (1C, dt, J 10.9 Hz, 3.7 Hz) 112.4 (1C, dd, J 20.8 Hz, 4.2
Hz); LCMS/[M+H]+: 144.3.
In summary, we have demonstrated an efficient methodology for
2
the synthesis of substituted H and 13C labeled benzaldehydes
2
with >99 % isotopic purity with complete transfer of H and
13C label into the -CHO group. LDA has been found to be an
efficient base for regio- selective deprotonation of 1,3-
disubstituted benzenes.
The synthetic methodology described represents a simple yet
versatile route to functionalized 2H and 13C-formyl
i
This paper is dedicated to Dr. Malcom MacCoss, Ph.D.
FRSC, USA.
benzaldehydes.
Applications of this methodology to the
synthesis of 3H and 14C labeled benzaldehydes and other
functionalized aromatics (viz., deuterated benzenes, acetyl
benzenes, deuterium embedded heterocylces) are in progress