Metal- and Acid-Free C-H Formylation of Nitrogen Heterocycles: Using Trioxane as an Aldehyde Equivalent Enabled by an Organic-Soluble Oxidant

Article abstract of DOI:10.1021/acs.orglett.8b02453

A metal-free, innate, and practical C-H formylation of nitrogen heterocycles using trioxane as a formyl equivalent is reported. This reaction provides a mild and robust method for modifying medicinally relevant heterocycles with an aldehyde handle. The use of an organic soluble oxidant, tetrabutylammonium persulfate, is critical in promoting the desired coupling.

Full text of DOI:10.1021/acs.orglett.8b02453

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Metal- and Acid-Free C−H Formylation of Nitrogen Heterocycles:
Using Trioxane as an Aldehyde Equivalent Enabled by an Organic-
Soluble Oxidant
Jacob M. Ganley,†
,⊥
Melodie Christensen, Yu-hong Lam, Zhengwei Peng, Angie R. Angeles,*
,
§
||
||
,‡,#
†
and Charles S. Yeung*
†
Department of Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States
Department of Process Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115,
‡
United States
§
Department of Process Research and Development, Merck & Co., Inc., 90 East Scott Avenue, Rahway, New Jersey 07065, United
States
|
|
Department of Modeling and Informatics, Merck & Co., Inc., 90 East Scott Avenue, Rahway, New Jersey 07065, United States
*
S Supporting Information
ABSTRACT: A metal-free, innate, and practical C−H
formylation of nitrogen heterocycles using trioxane as a
formyl equivalent is reported. This reaction provides a mild
and robust method for modifying medicinally relevant
heterocycles with an aldehyde handle. The use of an organic
soluble oxidant, tetrabutylammonium persulfate, is critical in
promoting the desired coupling.
itrogen-containing heterocycles are critically important
observation that weak C−H bonds α to an O atom can
N
to drug discovery and are prevalent in many modern
undergo activation through a photoredox catalysis activation
1
8
medicines. Rapid and reliable access to functionalized
heterocycles, therefore, greatly expedites the inventive process
of medicinal chemistry. To this end, aldehydes are versatile and
high-value functional handles that can be rapidly elaborated to
compounds of biological interest. Aldehydes are most
commonly synthesized through the reaction of organometallic
reagents with N,N-dimethylformamide (DMF) under cryo-
genic conditions (i.e., Bouveault reaction, Figure 1a) and the
mode culminated in a recent account of aldehyde synthesis by
9
a
the Doyle group. Inspired by this, we envisioned a
complementary approach that harnesses the direct activation
of weak C−H bonds in acetals and couples these intermediates
with a Minisci-type mechanism to achieve formylation of N-
heterocycles (Figure 2).
We selected isoquinoline as a model substrate for initial
8a
examination utilizing MacMillan’s conditions (Table 1). We
palladium-catalyzed reductive formylation of aryl halides
opted to examine trioxane as a formyl equivalent based on
2
(
Figure 1b). The direct carbonylation of C−H bonds is
4
Minisci’s report, which would simultaneously circumvent
perhaps the most atom economical way to construct aldehydes,
9
competing C−H cleavage at multiple sites. In the presence of
3
but catalytic accounts are sparse. In contrast, traditional
photocatalyst [Ir{dF(CF )ppy} (dtbpy)]PF (2 mol %),
3
2
6
methodologies such as the Vilsmeier−Haack and Duff
reactions depend on the intrinsic nucleophilicity of the
hetero)arene undergoing formylation due to the electrophilic
trifluoroacetic acid (TFA, 1 equiv), and sodium persulfate
Na S O ) under blue LED irradiation, we observed smooth
(
2
2
8
(
coupling of isoquinoline (1a) and totrioxane (2) to liberate
adduct 3a in 73% conversion by LCMS (entry 1). The
aromatic substitution mechanism at play. Inspired by early
4
accounts of open-shell alkyl radical additions, we identified an
addition of phase transfer catalyst tetrabutylammonium
important gap in formylation reactions of electron-deficient
n
5
chloride (N Bu
Cl) improved the yields slightly (entry 2).
4
heterocycles that leverages their innate reactivity. We herein
To our surprise, when the reaction was conducted in the
absence of the acid activator, comparable amounts of product
could be obtained (entry 3). We replaced Na S O with
report a metal-free, innate, and practical C−H formylation of
nitrogen heterocycles that uses trioxane as the formyl
equivalent (Figure 1c). Notably, this reaction is mild and
exhibits robust functional group tolerance.
2
2
8
n
10
tetrabutylammonium persulfate ((N Bu ) S O ) and ob-
4
2
2
8
served an improved conversion to 3a (entry 4), pointing to a
critical rate enhancement effect due to the homogeneous
The generation of free radicals α to a heteroatom (oxygen in
4
,6
particular) was originally described by Minisci in 1971.
These cross-dehydrogenative coupling (CDC) reactions have
7
seen a resurgence in recent years due to their potential
Received: August 1, 2018
positive impact on green and sustainable science. The
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02453
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Reaction Optimization: Coupling Isoquinoline
with Trioxane
a
a
yield 1a
(%)
yield 3a
(%)
entry
conditions
b
c
1
2
2 mol % 4, TFA, Na S O , MeCN/H O
27
4
73
79
2
2
8
2
b
c
n
c
2 mol % 4, TFA, Na S O , N Bu Cl,
2
2
8
4
CH Cl /H O
2
2
2
c
n
c
Figure 1. State-of-the-art methods in heterocycle formylation include
3
2 mol % 4, Na S O , N Bu Cl,
24
67
2
2
8
4
(
a) the Bouveault reaction and (b) the reductive carbonylation of aryl
CH
2 mol % 4, (N Bu ) S O , CH Cl
2
2 2 2
Cl /H O
n
c
halides. We herein propose (c) an innate C−H formylation using
trioxane under metal- and acid-free conditions.
4
5
6
<1
17
<1
86
68
86
4
2
2
8
2
n
c
(N Bu ) S O , CH Cl
4 2 2 8 2 2
n
c
(N Bu ) S O , DCE, 50 °C, no light
4
2
2
8
a
b
c
Conversion as determined by LCMS. 1 equiv. 2.5 equiv.
Conditions: isoquinoline (0.1 mmol), trioxane (1.5 mmol), solvent
0.2 M). All reactions (except entry 6) were conducted under Kessil
(
lamp irradiation.
Figure 2. Reaction design: using acetal radicals for innate C−H
formylation. The proposed mechanism involves H atom abstraction
with an external oxidant (eq 1), addition of the resulting radical to the
N-heterocycle (eq 2), spin-center shift of the adduct (eq 3), and
reoxidation with an external oxidant to liberate the desired product
(
eq 4).
nature of the coupling conditions. Surprisingly, the control
reaction in the absence of photocatalyst (but still with
irradiation) afforded 68% of the desired product (entry 5).
These results led us to speculate whether the O−O bond of
the persulfate anion alone was sufficient to promote coupling
between isoquinoline and trioxane. Since persulfate activation
is possible via transition metal redox chemistry, photochemical
7g,h,11
irradiation, and heat,
and with an eye toward the
practicality and general utility of this transformation, we
elected to explore thermal activation. To our delight, we
demonstrated that mild heating (50 °C) afforded the same
results in our desired formylation reaction (entry 6). In
contrast to Minisci’s account, which requires iron salts,
4
Figure 3. Reaction scope: coupling isoquinoline with trioxane.
stoichiometric TFA, and refluxing conditions, our protocol
Conditions: isoquinoline (0.4 mmol), trioxane (6 mmol), N-
is practical, metal- and acid-free, and occurs with gentle
heating. We expect that this important advance provides an
avenue for using sensitive heterocycles and functional groups
and will impact medicinal chemistry significantly.
n
(
[
Bu ) S O (1 mmol), DCE (0.2 M), 50 °C, 1−4 h. Isolated yields.
4
2
2
8
a] 5 mmol scale (∼1 g).
Next, we evaluated the generality of our metal-free C−H
formylation. A number of different isoquinolines undergo
productive coupling at the C1 position (Figure 3).
Importantly, in contrast to strategies involving organometallic
reaction conditions (3b−e). Although radical-type S Ar
12
N
reactions have been reported, we did not observe any
substitution of the C−Cl bonds (1d). Varying the electronic
character of the isoquinoline had minimal impact on reaction
efficiency, and functional groups including nitriles and esters
9
b
catalysts, aryl chlorides and bromides are inert under these
B
DOI: 10.1021/acs.orglett.8b02453
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
were tolerated (3f−i). We then turned our attention to other
medicinally relevant N-heterocycles (Figure 4). To our delight,
other bicyclic motifs undergo smooth coupling with trioxane,
including quinolines (3j−k), quinoxalines (3l), quinazolines
(3m), naphthyridines (3n), aza-indazoles (3o), and aza-
indoles (3p). We were likewise pleased to observe facile C−
H formylation of monocyclic structures, including pyridines
13
(
3q), pyrimidines (3r), and pyrazines (3s). In each of these
cases, no current methodologies provide rapid access to the
direct formylation products in synthetically useful yields. Also,
in contrast to methods involving transition metals, C−Cl and
C−Br bonds are preserved in our formylations, thus high-
lighting an important complementarity to photoredox
Figure 5. Divergent chemoselective formylation through a metalla-
9a
photoredox coupling (top) versus a metal-free radical addition
bottom).
(
9b
formylations (Figure 5).
In Minisci’s original paper, aryl-trioxane adducts were
provided the corresponding aldehydes in good yields (Figure
converted to their corresponding aldehydes in refluxing
6
), a hitherto unknown trioxane deprotection protocol.
To rationalize the site of observed C−H formylation of our
4
aqueous sulfuric acid. Importantly, unlike acetals or 1,3-
dioxanes (i.e., cyclic acetals), accounts of aryl-trioxanes are
extremely rare (<40 references) and these motifs are
underutilized as aldehyde synthons, although they exhibit
robust stability and hence are ideal for subsequent synthetic
manipulations. Mindful of the sensitive functional groups of
the various heterocycles examined above, we evaluated a
number of Lewis acids for hydrolysis of the trioxane functional
N-heterocycle scope, we conducted a series of computational
studies. Fukui indices are most commonly applied to predict
1
4
the site of free radical additions. Understanding the
regioselectivity of functionalization, however, is complicated
by the existence of multiple protonation states of N-
15
heterocycles. Of note, our method is independent of acidic
additives such as TFA. In the proposed reaction mechanism
(Figure 2), the putative trioxane radical undergoes addition to
the substrate, leading to dearomatization as governed by
group. Rare earth salts were ineffective (e.g., In(OTf) ), but a
3
simple protocol involving treatment with BCl for 10 min
3
+
−
orbital attractions. To our surprise, Fukui indices (f , f , and
0
16
f ) only successfully predicted the site of coupling <50% of
the time (see Supporting Information for details). Next, we
17
conducted density-functional theory (DFT) calculations to
shed further light on the origin of the observed regioselectivity.
Geometry optimizations and frequency calculations were
18
performed at the B3LYP/6-31G** level of theory, with
single-point energies evaluated at the B3LYP/6-311++G**
level. We opted to examine in greater detail the transition
structure for the addition event of the trioxane radical to two
model N-heterocycles, isoquinoline (1a) and 3-chloropyrazine-
2-carbonitrile (1s).
Figure 4. Reaction scope: coupling other heterocycles with trioxane.
Conditions: heterocycle (0.4 mmol), trioxane (6 mmol),
Figure 6. Conversion of aryl-trioxane adducts to aryl-aldehydes.
Conditions: BCl (2 equiv), CH Cl (0.5 M), 0 °C to rt, 10 min.
n
(
N Bu ) S O (1 mmol), DCE (0.2 M), 50 °C, 1−4 h. Isolated
4
2
2
8
3
2
2
yields. [a] Conducted with TFA (0.8 mmol).
Isolated yields.
C
DOI: 10.1021/acs.orglett.8b02453
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Based on our calculations, we confirmed that both the sense
and level of regioselectivities were well reproduced in
accordance with the experimental data. Our transition
structures show significant pyramidalization of the C under-
going radical addition. This step features an accessible
In conclusion, we have developed a robust protocol for the
C−H formylation of N-heterocycles using trioxane as the
aldehyde equivalent. Importantly, this reaction occurs under
mild reaction conditions and is devoid of precious metals and
n
stoichiometric acid additives. The use of N( Bu
)
4
S O
2
as a
2
8
‡
−1
activation barrier (Figure 7, ΔG ≈ 17−20 kcal mol ), and
soluble source of oxidant proved to be critical for success. We
anticipate that this method will continue to expand an ever-
growing toolbox of synthetic tools for medicinal chemists.
the regioisomeric transition states differ by at least 2.1 kcal
−
1
mol . For 1a, the energy difference between the regioisomeric
−
1
addition transition states (3.3 kcal mol ) is in line with the
ASSOCIATED CONTENT
Supporting Information
stability difference between the resulting radicals (3.1 kcal
■
−
1
mol ). In this case, C1 addition liberates a radical with two
benzenoid resonance structures, which is better stabilized
compared to C4 addition, which produces a radical with only
one resonance structure with an intact aromatic sextet. The
intramolecular 1,2-hydrogen shift (Figure 2, eq 3) was
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02453.
Experimental procedures, spectral data, computational
data (PDF)
‡
−1
predicted to have a high barrier (ΔG ≈ 44 kcal mol ) that
is inaccessible at 50 °C, although a bimolecular mechanism for
this shift cannot be ruled out as the shift is thermodynamically
downhill. Investigations to fully elucidate and characterize the
reaction mechanism are underway. Strategies to de novo predict
regioselectivity in our trioxane couplings (and in general) are
the subject of current studies, and will be reported in due
course.
AUTHOR INFORMATION
Corresponding Authors
■
*
*
E-mail: charles.yeung@merck.com.
E-mail: angie.angeles@gilead.com.
ORCID
Jacob M. Ganley: 0000-0001-7705-2886
Yu-hong Lam: 0000-0002-4946-1487
Charles S. Yeung: 0000-0001-7320-7190
Present Addresses
⊥Department of Chemistry, Princeton University, Frick
Chemistry Laboratory, Washington Road, Princeton, NJ
0
8540.
#
Department of Process Chemistry, Gilead Sciences, 333
Lakeside Drive, Foster City, CA 94404.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Rosina Ayore, Wilfredo Pinto, and Adam Beard
Merck) for collecting HRMS data. We thank Hai-Young Kim
Merck) for 2D NMR analysis. We thank Alexei Buevich,
■
(
(
Daniel DiRocco, David Witter, Jared Cumming, Tony Siu
Merck), and Vy Dong (UC Irvine) for helpful conversations.
(
We are grateful to the Merck 2016 Chemistry Internship
program, David Witter, Phieng Siliphaivanh, Nunzio Sciam-
metta, and Johnny Bennett (Merck) for their support of J.M.G.
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D
DOI: 10.1021/acs.orglett.8b02453
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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173−4178. (b) Pirnot, M. T.; Rankic, D. A.; Martin, D. B. C.;
MacMillan, D. W. C. Science 2013, 339, 1593−1596. (c) McNally, A.;
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(
13) Ma, Y.; Liang, J.; Zhao, D.; Chen, Y.-L.; Shen, J.; Xiong, B. RSC
Adv. 2014, 4, 17262−17264.
(
14) When we subjected simple unsubstituted heterocycles (e.g.,
pyridine, pyrimidine, pyrazine) to the reaction conditions, we
observed poor conversion to the desired coupling products and as
mixtures of regioisomers. We speculate that oxidation of the N atoms
E
DOI: 10.1021/acs.orglett.8b02453
Org. Lett. XXXX, XXX, XXX−XXX