Transition-Metal-Free Formylation of Allylzinc Reagents Leading to α-Quaternary Aldehydes

Article abstract of DOI:10.1021/acs.orglett.8b00360

The first example of formylation of allylzinc reagents using S-phenyl thioformate is presented. The reaction proceeded under mild conditions without any transition-metal catalyst, forming quaternary carbon centers with reactive functionalities, such as formyl and vinyl groups. Moreover, Barbier-type formylation of an allylic bromide with a sterically demanding thioformate was achieved. As a preliminary result, asymmetric formylation was conducted using a menthol-derived chiral thioformate.

Full text of DOI:10.1021/acs.orglett.8b00360

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Transition-Metal-Free Formylation of Allylzinc Reagents Leading to
α‑Quaternary Aldehydes
Ryosuke Haraguchi,* Akinori Kusakabe, Nakaba Mizutani, and Shin-ichi Fukuzawa*
Department of Applied Chemistry, Institute of Science and Engineering, Chuo University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo
112-8551, Japan
S
* Supporting Information
ABSTRACT: The first example of formylation of allylzinc
reagents using S-phenyl thioformate is presented. The reaction
proceeded under mild conditions without any transition-metal
catalyst, forming quaternary carbon centers with reactive
functionalities, such as formyl and vinyl groups. Moreover, Barbier-type formylation of an allylic bromide with a sterically
demanding thioformate was achieved. As a preliminary result, asymmetric formylation was conducted using a menthol-derived
chiral thioformate.
introducing formyl or imidoyl groups (Scheme 1, eq 4).8,9
Fujihara and Tsuji developed a method for the formylation of
arbon−carbon bond formation reactions are still of
Ccentral importance in organic synthesis. They are
allylcopper(I) species that were generated by borylcupration of
especially needed in the construction of quaternary carbon
centers, which has been recognized as one of the most
challenging tasks in synthetic chemistry because of the
difficulties associated with the repulsion of four carbon
substituents.1 However, quaternary carbon centers are indis-
pensable units found in many natural products and
pharmaceuticals.2 Therefore, the development of novel reagents
and catalysts for the construction of quaternary carbon centers
is a highly demanding but necessary synthetic task.
allenes (Scheme 2, eq 1).9a Moreover, Ohmiya and Sawamura
Scheme 2. Formylation and Imidoylation for the
Construction of Quaternary Carbon Centers
Aldehydes with quaternary carbons at the α-position are
useful building blocks of these centers because formyl groups
can be utilized for various C−C, C−N, and C−S bond
formation reactions.3 The most established approach to the
synthesis of α-quaternary aldehydes is the reaction of α,α-
disubstituted aldehydes with C-electrophiles (Scheme 1, eq
1).4,5 Other strategies employ carbon migration (Scheme 1, eq
2) or [3,3]-sigmatropic rearrangement (Scheme 1, eq 3) as an
efficient process for the preparation of these aldehydes.6,7
Most recently, two research groups presented an elegant
methodology for the preparation of α-quaternary aldehydes by
Scheme 1. Synthetic Strategy for the Preparation of α-
Quaternary Aldehydes
reported the catalytic asymmetric synthesis of α-quaternary
aldehydes through the reaction of in situ-generated
formimidoylcopper(I) species and allylic phosphates followed
by hydrolysis (Scheme 2, eq 2).9b In most of these strategies
(Scheme 1, eqs 1−4), catalysts play an important role in the
construction of quaternary carbon centers by lowering the
activation energy. Herein we describe the first example of
Received: January 31, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00360
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
formylation of allylzinc species with the use of S-phenyl
thioformate (Scheme 2, eq 3). The reaction proceeded without
any transition-metal catalyst under mild conditions, eventually
forming quaternary carbon centers. A variety of allylzinc
reagents were successfully employed in the formylation to
afford α-quaternary aldehydes bearing a terminal olefin.
Moreover, a Barbier-type formylation reaction of an allylic
bromide with a sterically demanding thioformate was achieved.
During the course of our research concerning catalytic
formylation of organozinc reagents,10 we focused on the
formylation of γ,γ-disubstituted allylzinc reagents. First, the
palladium-catalyzed formylation of allylzinc reagent 1a with 2a
was attempted under the optimized reaction conditions
previously employed for the formylation of arylzinc reagents,10
affording the formylated product 3a in 75% yield (see the
Supporting Information for details).
Table 2. Scope of Allylzinc Reagents
After extensive screening of different reaction conditions, it
was found that the reaction proceeded at −78 °C for 30 min
without any transition-metal catalyst, providing the desired
product 3a in 94% yield (Table 1, entry 1). The effects of the
Table 1. Formylation of Allylzinc Reagents: Effect of the
a
Reaction Parameters
c
b
entry
variation from the “standard” conditions
yield (%)
1
2
none
94
trace
16
0
HCOOEt instead of 2a
HCOOPh instead of 2a
DMF instead of 2a
2b instead of 2a
2c instead of 2a
2d instead of 2a
at −40 °C
3
4
5
93
94
94
61
60
35
6
7
8
9
at 0 °C
at 25 °C
10
a
Standard conditions: 1a (0.22 mmol) and 2a (0.20 mmol) in THF
b
(2.0 mL) at −78 °C for 30 min. Determined by 1H NMR analysis of
the crude mixture using dibromomethane as the internal standard.
c
Structures of 2b−d:
reaction parameters on the formylation are shown in Table 1.
The use of ethyl or phenyl formate as the formylating reagent
gave 3a in lower yield (Table 1, entries 2 and 3). Moreover,
when dimethylformamide (DMF) was employed instead of 2a,
no formation of the product was observed (Table 1, entry 4).11
In contrast, the use of thioformates 2b−d instead of 2a allowed
formation of the product in high yields (Table 1, entries 5−7).
However, increasing the reaction temperature led to a gradual
reduction in the reaction yield (Table 1, entries 8−10). From
thioformates 2a−d used in the screening study, 2a was selected
as an optimal formylating reagent because of its easy availability.
With the optimized reaction conditions in hand, the scope of
allylzinc reagents in the formylation reaction was examined next
(Table 2). Various allylzinc reagents with aryl and alkyl
a
Standard conditions: 1 (0.22 mmol) and 2a (0.20 mmol) in THF
b
(2.0 mL) at −78 °C for 30 min. Br·LiCl is represented as X for
c
d
e
clarity. Isolated yields. At −40 °C for 30 min. At 0 °C for 10 min.
f
g
h
At −85 °C for 30 min. At −100 °C for 1 h. Isolated yield as an
i
alcohol after reduction with NaBH4. Determined by 1H NMR analysis
of the crude mixture using dibromomethane as the internal standard.
substituents at the γ-position (Table 2, entries 1−12) were
utilized in this reaction to provide the corresponding α-
B
DOI: 10.1021/acs.orglett.8b00360
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
quaternary aldehydes.12 Both the presence of electron-donating
and electron-withdrawing groups at the para position of the
phenyl groups had little effect on the efficiency of the reaction
(Table 2, entries 2−4). However, when sterically demanding
allylzinc reagents were employed, the reaction temperature had
to be increased for thioformate 2a to be completely consumed
(Table 2, entries 5, 6, and 9). In contrast, in the case of 1k and
1l, which are not sterically demanding, the reaction temperature
was decreased to −85 or −100 °C in order to suppress the
decomposition of the products. Because of a problem
associated with instability toward silica gel column chromatog-
raphy, alcohol 3k′ was obtained as a product after reduction
with sodium borohydride (Table 2, entry 11).
As a preliminary result, we carried out the asymmetric
formylation of allylzinc reagents using chiral thioformate 2e,
which was prepared from menthol in three steps. The synthetic
route to 2e and the respective procedure are shown in the
Supporting Information. Thioformate 2e was reacted with
allylzinc reagent 1a under the optimized reaction conditions,
affording (−)-3a in 44% yield with 34% ee (Scheme 4). In spite
of the low enantioselectivity, this result indicated the potential
to expand this formylation method to the asymmetric version.
Scheme 4. Asymmetric Formylation of an Allylzinc Reagent
Using a Chiral Thioformate
In order to enhance the practicality of this formylation
method, the Barbier-type formylation of allylic bromide 4 with
2a was investigated. In the reaction, zinc dust and lithium
chloride converted allylic bromide 4 to allylzinc reagent 1a,
which then reacted with 2a to afford the formylated product 3a.
However, product 3a was obtained in only 30% yield when
compound 4 was reacted with an equimolar amount of 2a at
room temperature for 1 h (Table 3, entry 1). This
In summary, we have developed the first example of
formylation of allylzinc reagents with S-phenyl thioformate.
This protocol enabled the construction of quaternary carbon
centers with a formyl group and a terminal olefin. Moreover,
studies showed that various allylzinc reagents could be
successfully utilized in this reaction. In addition, Barbier-type
formylation of an allylic bromide with a sterically demanding
thioformate was achieved. Finally, preliminary investigations of
the asymmetric formylation were conducted using a menthol-
derived chiral thioformate. Future work will be devoted to the
design of effective chiral thioformates to improve the
enantioselectivity of the asymmetric formylation.
Table 3. Barbier-Type Formylation of Allylic Bromide 4 with
a
Thioformate 2
b
b
entry
2
yield of 5 (%)
yield of 3 (%)
1
2
3
4
2a
2b
2c
2d
2d
16
34
17
9
30
0
26
46
73
ASSOCIATED CONTENT
* Supporting Information
■
c
S
5
35
a
Standard conditions: 4 (0.20 mmol) and 2 (0.20 mmol) in THF (2.0
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00360.
b
1
mL) at room temperature for 1 h. Determined by H NMR analysis
of the crude mixture using dibromomethane as the internal standard.
c
The amounts of 4 and zinc dust were increased to 0.40 and 0.60
Detailed experimental procedures and compound char-
acterization data (PDF)
mmol, respectively.
disappointing result was a consequence of the formation of
allylic sulfide 5, which was caused by the reaction of 4 and in
situ-generated zinc thiolate 6 (Scheme 3). We envisioned that
AUTHOR INFORMATION
Corresponding Authors
■
*ryo1229@kc.chuo-u.ac.jp
*orgsynth@kc.chuo-u.ac.jp
Scheme 3. Formation of Byproduct 5
ORCID
Ryosuke Haraguchi: 0000-0001-6703-8036
Shin-ichi Fukuzawa: 0000-0001-8108-3829
Notes
The authors declare no competing financial interest.
the appropriate choice of S substituent on thioformate 2 could
suppress this side reaction to some extent. Therefore, the
effects of changing thioformate 2 were investigated (Table 3).
Among the reagents employed, mesityl-substituted thioformate
2d with a sterically demanding substituent gave the best result
(Table 3, entry 4). Nitro-substituted 2b was decomposed by
zinc dust and lithium chloride, resulting in no formation of the
desired product 3a (Table 3, entry 2). Finally, the use of 2
equiv of allylic bromide 4 with 2d afforded product 3a in 73%
yield.
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Organic Letters
Letter
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DOI: 10.1021/acs.orglett.8b00360
Org. Lett. XXXX, XXX, XXX−XXX