Catalytic Regioselective γ-Methylenation of α,β-Unsaturated Aldehydes Using Formaldehyde via Vinylogous Aldol Condensation

Article abstract of DOI:10.1021/acs.orglett.8b04110

The first vinylogous aldol condensation of α,β-unsaturated aldehydes using aqueous formaldehyde is developed under mild reaction conditions to form the γ-methylenated products with excellent regioselectivity. Using this methodology, a short synthesis of α-triticene, an antifungal compound, is achieved in two steps. The practicality of this methodology is demonstrated by the gram-scale synthesis. Formation of the unusual double γ-functionalized products from crotonaldehyde and a direct asymmetric vinylogous aldol product from phenylglyoxal is also described.

Full text of DOI:10.1021/acs.orglett.8b04110

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Catalytic Regioselective γ‑Methylenation of α,β-Unsaturated
Aldehydes Using Formaldehyde via Vinylogous Aldol Condensation
Mahesh S. Kutwal, Sachin Dev, and Chandrakumar Appayee*
Discipline of Chemistry, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar, Gujarat 382355, India
*
S Supporting Information
ABSTRACT: The first vinylogous aldol condensation of α,β-
unsaturated aldehydes using aqueous formaldehyde is
developed under mild reaction conditions to form the γ-
methylenated products with excellent regioselectivity. Using
this methodology, a short synthesis of α-triticene, an
antifungal compound, is achieved in two steps. The
practicality of this methodology is demonstrated by the
gram-scale synthesis. Formation of the unusual double γ-functionalized products from crotonaldehyde and a direct asymmetric
vinylogous aldol product from phenylglyoxal is also described.
1
ormaldehyde is used as a one-carbon electrophile in
several organic transformations to functionalize alde-
Scheme 1. Methylenation of α,β-Unsaturated Aldehydes
F
Using Formaldehyde
2
3
4
1c,5
hydes, ketones, amines, and alkenes.
However, the
reaction of formaldehyde with α,β-unsaturated aldehydes has
6
rarely been studied. In 1953, Pummerer and co-workers tested
the reaction of formaldehyde with crotonaldehyde catalyzed by
NaOAc and found the formation of a α-methylenated product
that further self-reacted to produce a cycloadduct via Diels−
6a
Alder reaction (Scheme 1). After a decade, Farberov and co-
workers carefully chose an α-methylated α,β-unsaturated
aldehyde (to avoid α-functionalization) for the Mannich
reaction with diethylammonium chloride and formaldehyde
to obtain a γ-aminomethylated product that underwent
thermal elimination at high temperature and high vacuum to
6b
give a γ-methylenated product. Though the unsaturated
carbonyl compounds such as ketones, esters, and lactones have
been extensively studied for the vinylogous aldol reaction
7
a−c
7d
involving silyl ethers
and dienamine intermediates, α,β-
8
unsaturated aldehydes have rarely been explored. To the best
of our knowledge, there is no report in the literature for the
vinylogous aldol reaction (or condensation) of formaldehyde
with α,β-unsaturated aldehydes.
On the other hand, formation of a regioisomeric mixture of
9
products was reported for the S -type alkylation of α,β-
N
10
unsaturated aldehydes through dienamine catalysis. Recently,
we disclosed a highly regio- and enantioselective γ-alkylation of
α,β-unsaturated aldehydes in the presence of TFE (trifluor-
oethanol). In continuation of our interest in achieving a
highly regioselective vinylogous γ-functionalization, we further
envisaged a γ-hydroxymethylation of α,β-unsaturated alde-
hydes using formaldehyde via the vinylogous aldol reaction.
Accordingly, (E)-dec-2-enal 1e was treated with aqueous
1
1
21% yield via the vinylogous aldol condensation (Table 1,
entry 1).
Several catalysts (2b−m) were tested for the reaction of
aqueous formaldehyde with α,β-unsaturated aldehyde 1e, and
formaldehyde in the presence of catalyst 2a and PhCO H in
2
toluene and TFE.
The expected γ-hydroxymethylated product 3e was not
Received: December 24, 2018
observed; instead, a γ-methylenated product 4e was formed in
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b04110
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a,b
Table 1. Optimization of the Reaction Conditions
Scheme 2. Substrate Scope
temp
(°C)
time
(h)
yield of 4e
b
entry
solvent
acid
(%)
1
2
3
4
5
6
7
8
9
toluene/TFE
toluene/TFE
toluene/TFE
toluene/TFE
toluene
PhCO H
4-NBA
TFA
rt
rt
rt
rt
rt
rt
0
0
0
0
0
48
48
48
48
74
24
72
48
66
60
36
60
21
30
c
35
d
14
43
c
48
61
20
50
2
AcOH
d
toluene
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
toluene/TFE
MTBE/TFE
CH Cl /TFE
2
2
e
10
11
12
CHCl /TFE
3
d
H O/TFE
2
f
CHCl /TFE
0
3
a
Reactions were performed with 1e (37 μL, 0.2 mmol), formaldehyde
49 μL of 37% aq solution, 0.6 mmol), catalyst 2a (13 mg, 0.04
mmol), and acid (0.1 mmol) in solvent (1 mL) and TFE (77 μL)
(
b
1
unless otherwise mentioned. Determined by H NMR analysis using
c
d
1
,3-dinitrobenzene as an internal standard. No reaction. Unidenti-
e
fied mixture of products was formed. Isolated yield after column
f
chromatography. Formaldehyde (19.5 μL of 37% aq solution, 0.24
mmol) was used. 4-NBA = 4-nitrobenzoic acid.
unsatisfactory results were obtained (see the Supporting
Information). During the acid screening (entries 2−4),
AcOH was found to produce 4e in a higher yield (entry 4).
Undesired results were obtained when the reaction was carried
out without TFE and AcOH (entries 5 and 6). To avoid the
major decomposition of 1e, the reaction was performed at 0
a
Reactions were performed with 1 (0.2 mmol), formaldehyde (49 μL
of 37% aq solution, 0.6 mmol), catalyst 2a (13 mg, 0.04 mmol), and
°
C and the product 4e was formed in 43% yield (entry 7).
Among the solvents screened in the reaction (entry 8−11), a
AcOH (6 μL, 0.1 mmol) in CHCl (1 mL) and TFE (77 μL) unless
3
b
otherwise mentioned. Isolated yield after column chromatography.
c
d
mixture of CHCl /TFE (13:1) was found to be a suitable
Catalyst 2a (10 mol %) was used. Crude aldehydes 4o and 4p were
3
solvent that led to the γ-methylenated product 4e as a single
regioisomer in 61% isolated yield (entry 10). When 1.2 equiv
of aqueous formaldehyde was added, the product 4e was
observed in 50% yield (entry 12).
reduced to alcohols 5o and 5p, respectively, using NaBH (74 mg, 2
mmol). Catalyst 2a (30 mol %) was used.
4
e
After the successful optimization of the reaction conditions
for the formation of γ-methylenated product 4e, the substrate
scope of α,β-unsaturated aldehydes 1 was investigated. α,β-
Unsaturated aldehyde 1a containing an ester functional group
smoothly reacted with formaldehyde to give the γ-methylen-
ated product 4a in 42% isolated yield (Scheme 2). α,β-
Unsaturated aldehydes 1b−d containing different alkyl chain
lengths were reacted with aqueous formaldehyde under the
optimized reaction conditions to result the γ-methylenated
products 4b−d in a moderate yields. The γ-methylenated
products 4e−g obtained from the reaction of formaldehyde
with α,β-unsaturated aldehydes having longer alkyl chain
lengths (1e−g) were isolated with moderate yields.
vinylogous γ-methylenation. α,β-Unsaturated aldehyde 1o
was subjected to vinylogous γ-methylenation, and due to the
volatile nature of the product 4o (molecular weight = 96), it
was in situ reduced to the corresponding alcohol 5o using
NaBH before further characterization. Under similar reaction
4
conditions, α,β-unsaturated aldehyde 1p was converted to 5p
in 40% yield. The reactions of α,β-unsaturated aldehyde 1e
with acetaldehyde, isobutyraldehyde, or 4-nitrobenzaldehyde
under the optimized reaction conditions was unsuccessful, and
a major decomposition of 1e was noticed.
As a part of the substrate scope, we envisaged an application
12
of this methodology for a short synthesis of α-triticene, an
antifungal compound isolated from cereal seeds, starting from
commercially available dodecanal 6 in two steps. Thus,
dodecanal 6 was reacted with the Wittig reagent 7 at 85 °C
The substrates containing a terminal olefin (1h), Z-olefin
1i), and the benzyl group (1j) were smoothly converted to
(
1
3
the γ-methylenated products. Functional groups such as silyl
ether (1k), benzyl ether (1l and 1m), and thioether (1n) in
the substrates are found to be compatible during the
to form (E)-tetradec-2-enal 1q in 64% isolated yield.
Vinylogous aldol condensation of α,β-unsaturated aldehyde
1q using formaldehyde under the optimized reaction
B
DOI: 10.1021/acs.orglett.8b04110
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Organic Letters
Letter
conditions resulted α-triticene (4q) in 70% yield as a single
regioisomer (Scheme 3).
treated with a Wittig reagent 15 to obtain a conjugated ester
16 in 61% isolated yield.
Scheme 3. Regioselective Short Synthesis of α-Triticene
Scheme 5. Derivatization of γ-Methylenated Product
(
4q)
When formaldehyde was treated with crotonaldehyde 1r, the
γ-methylenated product was not observed. Unexpectedly, the
double γ-functionalized products 8 with a trifluoroethoxy
group and 9 with an acetate group were obtained in 15% and
2
6% yields, respectively (Scheme 4). On the other hand, the β-
Scheme 4. Reaction of Formaldehyde with Other α,β-
Unsaturated Aldehydes
To show the scalability of this methodology with the
commercially available reagents and catalyst, a gram-scale
reaction of 1g (1.87 g) with aqueous formaldehyde (3 equiv)
catalyzed by 2a was performed to achieve the γ-methylenated
product 4g (1.2 g) in 61% isolated yield (Scheme 6).
Scheme 6. Gram-Scale Synthesis of Product 4g
When α,β-unsaturated aldehyde 1e was treated with
phenylglyoxal 17 instead of formaldehyde, a vinylogous aldol
product 18 was observed in 31% yield and 30% ee along with
an unidentified mixture of products (Scheme 7). Further
reaction optimization using a variety of secondary amine
catalysts, acid additives, and solvents (see the Supporting
Information) led to a higher ee of the product 18 (92% ee)
using the catalyst 2c, but we were unable to increase the
substituted compound 10 (E-isomer) resulted in product 11
Scheme 7. Enantioselective Vinylogous Aldol Reaction of
α,β-Unsaturated Aldehyde 1e
(Z-isomer) in 25% yield (very slow reaction) along with an
inseparable mixture of products. The conversion of the E-
isomer 10 to the Z-isomeric product 11 (assigned based on the
COSY and NOE experiments, see the Supporting Information)
could be possible through a C−C bond rotation at the
enamine intermediate with the catalyst 2a. When the γ-
substituted α,β-unsaturated aldehyde 12 was subjected to the
optimized reaction conditions, a α-methylenated product 13
was obtained in 32% yield, and no trace of the γ-functionalized
product was observed. 2-Methyl-2-pentenal (α-Substituted
α,β-unsaturated aldehyde) was found to be unreactive under
the optimized reaction conditions.
To demonstrate the synthetic utility of this methodology,
α,β-unsaturated aldehyde 1g was converted to the methylen-
14
ated alcohol 5g, which was used as a diene for the Diels−
Alder reaction with N-phenylmaleimide to form a Diels−Alder
adduct 14 in 66% isolated yield from the diastereomeric
mixture (9:1) of products (Scheme 5). To extend the
conjugation further, the γ-methylenated product 4g was
C
DOI: 10.1021/acs.orglett.8b04110
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Letter
product yield. When α,β-unsaturated aldehyde 1b or 1i was
treated with phenylglyoxal 17, we were unable to purify the
vinylogous aldol product from the unidentified mixture of
products. The relative stereochemistry of the alcohol 18 was
assigned on the basis of the COSY and NOE experiments (see
the Supporting Information).
On the basis of the reaction results, a reaction mechanism is
proposed for the regioselective γ-methylenation of α,β-
unsaturated aldehydes in Scheme 8. Accordingly, catalyst 2
The practicality of this methodology is demonstrated by the
gram-scale synthesis of the γ-methylenated product 4g. On the
basis of the reaction results, a reaction mechanism is proposed
for the formation of the γ-methylenated products. However,
further studies are required to understand the role of TFE in
the regioselective γ-methylenation of α,β-unsaturated alde-
hydes. A vinylogous aldol reaction of α,β-unsaturated aldehyde
1e with phenylglyoxal 17 to form product 18 is described.
Further reaction optimization to improve the yield of the
vinylogous aldol product 18 is currently underway in our
laboratory.
Scheme 8. Proposed Mechanism for the γ-Methylenation of
α,β-Unsaturated Aldehydes
ASSOCIATED CONTENT
■
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b04110.
Complete experimental procedures and characterization
of new products, NMR spectra, and HPLC chromato-
grams (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: a.chandra@iitgn.ac.in.
ORCID
Chandrakumar Appayee: 0000-0003-1165-4918
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the SERB, India, for Extra Mural Research
funding (EMR/2014/000207) and IIT Gandhinagar for
financial support.
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