Two Types of Cross-Coupling Reactions between Electron-Rich and Electron-Deficient Alkenes Assisted by Nucleophilic Addition Using an Organic Photoredox Catalyst

Article abstract of DOI:10.1021/acs.joc.8b02025

Two types of photoreactions between electronically differentiated donor and acceptor alkenes assisted by nucleophilic addition using an organic photoredox catalyst efficiently afforded 1:1 or 2:1 cross-coupling adducts. A variety of alkenes and alcohols were employed in the photoreaction. Control of the reaction pathway (i.e., the formation of the 1:1 or 2:1 adduct) was achieved by varying the concentration of the alcohol used. Detailed mechanistic studies suggested that the organic photoredox catalyst acts as an effective electron mediator to promote the formation of the cross-coupling adducts.

Full text of DOI:10.1021/acs.joc.8b02025

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Featured Article
Two types of cross-coupling reactions between
electron-rich and electron–deficient alkenes assisted by
nucleophilic addition using an organic photoredox catalyst
Yosuke Tanaka, Suzuka Kubosaki, Kazuyuki Osaka, Mugen Yamawaki, Toshio Morita, and Yasuharu Yoshimi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02025 • Publication Date (Web): 03 Sep 2018
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Two types of cross-coupling reactions between electron-rich and electron–deficient
alkenes assisted by nucleophilic addition using an organic photoredox catalyst
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Yosuke Tanaka, Suzuka Kubosaki, Kazuyuki Osaka, Mugen Yamawaki, Toshio Morita,
Yasuharu Yoshimi*
Department of Applied Chemistry and Biotechnology, Graduate School of Engineering,
University of Fukui, 3ꢀ9ꢀ1 Bunkyo, Fukui 910ꢀ8507, Japan
Eꢀmail of corresponding author: yyoshimi@uꢀfukui.ac.jp
Table of Contents
X
OR'
ν
h
RO
BP, DCN
+R'OH,
X
1:1 adduct
RO
RO
X
X = CN, CO2CH3,
CONH2, .......
OR
RO
NC
CN
DCN:
BP:
OR'
2:1 adduct
Abstract
Two types of photoreactions between electronicallyꢀdifferentiated donor and acceptor alkenes
assisted by nucleophilic addition using an organic photoredox catalyst efficiently afforded 1:1 or
2:1 crossꢀcoupling adducts. A variety of alkenes and alcohols were employed in the
photoreaction. Control of the reaction pathway (i.e., the formation of the 1:1 or 2:1 adduct) was
achieved by varying the concentration of the alcohol used. Detailed mechanistic studies
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suggested that the organic photoredox catalyst acts as an effective electron mediator to promote
the formation of the crossꢀcoupling adducts.
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Introduction
Crossꢀcoupling reactions between alkenes are increasingly attracting attention for use in the
construction of molecular framework because the simple alkenes starting materials are
commercially available, inexpensive, or readily prepared.1 For example, an elegant Feꢀcatalyzed
crossꢀcoupling reaction between electronicallyꢀdifferentiated donor and acceptor alkenes with
phenylsilane was reported by P. S. Baran (Scheme 1a).2 This type of coupling is rare because
copolymerization between the alkenes is a common occurrence. In this reaction, alkyl radical,
which was generated from the electronꢀrich alkene by hydrofunctionalization using an Fe
catalyst and silane at 60 °C, reacted with the electronꢀdeficient alkene to afford coupling
product after reduction of the adduct radical. This type of crossꢀcoupling reaction has become a
powerful and versatile tool for the transformation of alkenes to complex molecules,3 and milder
conditions and a more environmentally friendly method for the crossꢀcoupling reaction, such as
reaction without heating and metal, is desirable.
We have recently reported on the photoinduced decarboxylative radical addition of carboxylic
acids to alkenes by organic photoredox catalysts such as a combination of phenanthrene (Phen)
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and 1,4ꢀdicyanobenzene (DCB), or biphenyl (BP) and 1,4ꢀdicyanonaphthalene (DCN) through
photoinduced electron transfer (PET).4 When assessing the influence of the nature of the alkene
on the photoinduced decarboxylative radical addition, we observed that the photoinduced
crossꢀcoupling reaction assisted by nucleophilic addition between electronꢀrich and
electron–deficient alkenes took place efficiently via PET5,6 (Scheme 1b). The study described
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below
has
demonstrated
the
new
strategy
for
crossꢀcoupling
between
electronicallyꢀdifferentiated alkenes employing organic photoredox catalysts under mild
conditions, and the successful control of the formation of two types of crossꢀcoupling products
(1:1 or 2:1 adducts) by varying the concentration of nucleophile (R’OH).
Scheme 1. Crossꢀcoupling reactions between electronꢀrich and electronꢀdeficient alkenes
a. Fe-catalyzed cross coupling reaction (2014, Baran)
O
O
Fe(dibm)3, PhSiH3
60 oC/EtOH
OTBS
OTBS
TBSO
H
H
b. This work
X
BP:
OR'
ν
h
RO
DCN: NC
CN
BP, DCN
1:1 adduct product
+
RO
X
CH3CN/R'OH
X
X = CN, CO2CH3,
CONH2, .......
OR
OR'
RO
2:1 adduct product
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Results and Discussion
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Optimization of the photoinduced crossꢀcoupling reaction between dodecyl vinyl ether 1a as
an electronꢀrich alkene and acrylonitrile 2A as an electronꢀdeficient alkene using organic
photoredox catalysts was carried out (Table 1). Irradiation of an aqueous acetonitrile solution
(CH3CN/H2O=9:1) containing 1a (20 mM), 2A (20 mM), BP (5 mM, 25 mol%), and DCN (5
mM, 25 mol%) in Pyrex vessel (15 x 180 mm) under argon atmosphere using a 100 W
highꢀpressure mercury lamp (>280 nm) for 5 h at room temperature led to the formation of
crossꢀcoupling product 3aA as a racemic mixture in 72% yield (Entry 1, Table 1). Photoreaction
using lower concentrations of BP (1 mM, 5 mol%) and DCN (1 mM, 5 mol%) and employing
longer irradiation times (24 h) were found to produce 3aA in the similar yield (66%, Entry 2). In
the absence of light, water, DCN, and both BP and DCN, 3aA was not generated (data not
shown). However, with light, water, and DCN but in the absence of BP, a 2% yield of 3aA was
observed (Entry 3). The use of Phen and DCB or Phen and DCN instead of BP and DCN
decreased the yield of 3aA (Entries 4 and 5), because the photoreaction sideꢀproducts such as
[2+2] cycloadducts between Phen and 1a were obtained. The blue LED (18 W, 405 nm) derived
visible lightꢀinduced reaction of 1a (20 mM) and 2A (20 mM) using BP (2 mM) and
9,10ꢀdicyanoanthracene (DCA, 2 mM) for 24 h also led to decreased yield of 3aA (35%, Entry
6). The use of aqueous DMF or DMSO (DMF/H2O or DMSO/H2O=9:1) as the solvent in the
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place of aqueous acetonitrile failed to produce the adduct 3aA, and the use of aqueous acetone
(acetone/H2O=9:1) resulted in a reduced yield of 3aA (Entry 7). Increasing the proportion of
water in the aqueous acetonitrile gradually decreased the yield of 3aA (Entries 8 and 9,
CH3CN/H2O=7:3 and 5:5) due to the low solubilities of 1a and DCN in water. Thus, the highest
yield of 3aA from the photoreaction of 1a and 2A was observed using BP and DCN as the
organic photoredox catalyst and aqueous acetonitrile (CH3CN/H2O=9:1) as the solvent.
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Table 1. Photoinduced crossꢀcoupling reaction between 1a and 2A assisted by water addition.
CN
ν
h , 5 h
Photocatalyst
+
11O
CN
OH
CH3CN/H2O=9:1
11O
1a (20 mM)
2A (20 mM)
3aA
Entry
Photocatalyst
3aA
/%
Yield of
BP (5 mM), DCN (5 mM)
BP (1 mM), DCN (1 mM)
1
2a
72
66
DCN (5 mM)
3
2
Phen (5 mM), DCB (5 mM)
Phen (5 mM), DCN (5 mM)
BP (2 mM), DCA (2 mM)
BP (5 mM), DCN (5 mM)
BP (5 mM), DCN (5 mM)
BP (5 mM), DCN (5 mM)
4
5
6b
7c
8d
9e
45
46
35
58
66
12
aIrradiation time was 24 h. bVisible blue LED (405 nm) was used as light source, and irradiation time
was 24 h. cAcetone/H2O=9:1. dCH3CN/H2O=7:3. eCH3CN/H2O=5:5.
The scope and limitations of the electronꢀrich alkenes were then explored (Table 2). A variety
of vinyl ethers such as ethyl vinyl ether 1b, tꢀbutyl vinyl ether 1c, 3,4ꢀdihydroꢀ2Hꢀpyran 1d,
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3ꢀphenylpropyl vinyl ether 1e, and 2ꢀhydroxyethyl vinyl ether 1f reacted with 2A under the
optimized photochemical conditions, providing crossꢀcoupling adducts 3bA–fA as racemic and
diastereomeric mixtures in good yields. In the case of 1d, the regioisomers (3dA’ and 3dA)
were observed, as was the case in a similar photoinduced nucleophilic addition.6 The
observation of good yield of 3fA shows that a hydroxy group in 1 is tolerated in this
photoreaction. In comparison with the products from 1a,b,e, and f, the product 3cA from tꢀbutyl
vinyl ether 1c was obtained in a slightly higher yield because a slightly more electronꢀrich
radical was generated (see intermediate 16 in the plausible mechanism described in Scheme 4).
The tetraꢀ, and triꢀsubstituted alkenes 1g,h provided good yields of 3gA,hA, respectively, and
the photoreaction of cyclohexene 1i provided a similar yield of 3iA, even though an increased
concentration of DCN (10 mM) was required. In constrast, the photoreaction of
methylenecyclohexane 1j resulted in significantly decreased product yield, even with an
increased concentration of DCN (10 mM). The use of diꢀsubstituted alkene ((Z)ꢀ2ꢀnonenꢀ1ꢀol)
1k, the lessꢀsubstituted alkene (1ꢀhexene) 1l, and allyl alcohol 1m resulted in no reaction,
indicating the photoreaction is strongly dependent on the oxidation potential of the electronꢀrich
alkenes (oxidation potential vs. SCE in acetonitrile: 1b +1.99 V, 1g +1.56 V, 1h +2.08 V, 1i
+2.25 V, 1j +2.62 V, 1l +2.85 V)7. When ethyl vinyl thioether 1n was subjected to the
photoreaction, crossꢀcoupling product 3nA was obtained in a significantly lower yield, because
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the highly reactive thioether 3nA under the photochemical conditions gave the secondary
photoproduct. The use of tꢀbutyl vinylcarbamate 1o and styrene 1p as the electronꢀrich alkene
resulted in a complex mixture. Thus, a variety of vinyl ethers and alkyl substituted alkenes can
be employed as the electronꢀrich alkene for the photoinduced crossꢀcoupling, with the exception
of those having a high oxidation potential or having high reactivity under the photochemical
conditions.
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Table 2. Scope of electronꢀrich alkene 1 in the photoreaction with 2A.
CN
ν
h , 5 h
BP (5 mM)
DCN (5 mM)
+
R
CN
OH
3bA-nA
CH3CN/H2O=9:1
R
2A (20 mM)
1b-j (20 mM)
CN
CN
OH
CN
OH
5
O
OH
5
OH
O
CN
OH
O
O
1k
1l
:
1
3bA (65%)
3cA (79%)
3dA' + 3dA (81%)
CN
CN
CN
OH
1m
OH
OH
HO
OH
O
O
3eA (65%)
3fA (65%)
3gA (74%)
BocHN
CN
CN
1o
1p
CN
CN
OH
OH
OH
OH
S
3jA (32%)a
3nA (9%)
3iA (69%)a
3hA (72%)
dr=86:14
aBP (5 mM) and DCN (10 mM) were used as the photocatalyst.
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To determine the scope of the electronꢀdeficient alkene, we explored the reactions of 1a,c
with methyl acrylate 2B, ethyl acrylate 2C, tꢀbutyl acrylate 2D, acrylic acid 2E, acrylamide 2F,
Nꢀtꢀbutyl acrylamide 2G, and crotononitrile 2H under the same photochemical conditions
(Table 3). The use of the relatively poorly electronꢀdeficient alkenes 2B–H in the place of 2A
led to lower yields of products 3aB–cH along with the formation of polymeric materials as
previously reported by us.8 In the case of 2E, a secondary photoreaction (photoinduced
decarboxylation) of the photoproduct 3aE took place to decrease the yield of 3aE, and the yield
was improved by carrying out the reaction for a shorter time (4 h). Similar to the results seen in
Table 2, slightly increased yields of 3cB–cD were observed using 1c as the electronꢀrich alkene
in comparison with those using 1a. The combined results show that a variety of electronꢀrich
and electronꢀdeficient alkenes can efficiently participate in the formation of crossꢀcoupling
product 3 using the organic photoredox catalyst.
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Table 3. Scope of electronꢀdeficient alkene 2 in the photoreaction with 1a or 1c.
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9
X
ν
h , 5 h
BP (5 mM)
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DCN (5 mM)
R"O
+
X
OH
3aB-cH
CH CN/H O=9:1
R"O
3
2
1a: R"= CH3(CH2)11
1c: R"=t-Bu
2B-H (20 mM)
(20 mM)
CO2Me
CO2Et
OH
CO2H
OH
CO2t-Bu
OH
OH
R"O
R"O
11O
R"O
3aB (46%)
3aC (46%)
3aD (47%)
3cD
(51%)
3aE (34%)a
3cB
3cC
(50%)
(50%)
CONH2
CONHt-Bu
CN
OH
OH
OH
11O
11O
R"O
3aF (51%)
3aG (48%)
3aH (20%)
3cH
(21%)
aIrradiation time was 4 h.
To elucidate the roll of the nucleophile, photoreactions of 1a,c with 2A in a 9:1 solvent mixture
of acetonitrile and an alcohol such as MeOH, EtOH, iꢀPrOH, and tꢀBuOH were carried out
(Table 4). Similar yields of 4aA,cA were obtained in the photoreactions of 1a,c using MeOH
instead of water. The yields of coupling products 5aA–7cA were strongly dependent on the
steric hindrance of both 1 and the alcohol used. In fact, the photoreaction of the hindered vinyl
ether 1c was strongly affected by the steric hindrance of tꢀBuOH to cause the low yield of 7cA.
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Table 4. Scope of the nucleophile in the photoinduced crossꢀcoupling reactions of 1a,c with 2A.
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8
9
ν
CN
h , 5 h
BP (5 mM)
DCN (5 mM)
10
11
12
13
14
15
16
17
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19
20
21
22
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1a,c
(20 mM)
2A
(20 mM)
+
OR'
CH3CN/R'OH=9:1
R"O
4-7
CN
CN
CN
CN
OMe
OEt
Ot-Bu
Oi-Pr
R"O
R"O
R"O
7aA (58%)
7cA
R"O
5aA (72%)
5cA
6aA (67%)
6cA
(30%)
4aA (76%)
(22%)
4cA
(41%)
(78%)
We next determined if a low concentration of alcohol could promote this reaction (Table 5).
The photoreaction of 1a (20 mM) and 2A (20 mM) in the presence of a low concentration of
alcohol (MeOH, 200 mM) as the nucleophile in dry acetonitrile led to the surprising formation
of 2:1 adduct 8aA. Optimization of the concentrations of 1a and 2A (1a: 20 mM, 2A: 10 mM)
resulted in a high yield of 8aA (88%). Similar photoreactions of 1a,c (20 mM) and 2A,B (10
mM) in the presence of a low concentration of alcohols (MeOH, EtOH, and iꢀPrOH: 200 mM)
provided 2:1 adducts 8cA–11aA. Similar to the abovementioned trends, the use of poorly
electronꢀdeficient alkenes such as 2B and more sterically hindered alcohols such as iꢀPrOH
decreased the yield of the adducts. When water was used as a nucleophile, aldehydes 12aA–cB
were obtained through the formation of hemiacetal 13 (Table 6). In contrast, the use of alkyl
substituted alkenes 1g,h in the place of vinyl ethers 1a,c with a low concentration of water did
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not lead to the formation of the 2:1 adduct (Scheme 2); instead, 1g formed the substituted
cyanonaphthalene 14 in 19% yield based on DCN and 1h formed the 1:1 adduct 3hA in the
almost same yield as that with higher amount of water (Table 2). Thus, the formation of 2:1
adducts was observed only in the photoreaction of vinyl ethers with a low concentration of the
nucleophile.
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Table 5. Formation of 2:1 adducts 8ꢀ11 in the photoreaction of 1 and 2 with a low concentration
of R’OH.
ν
h , 5 h
BP (5 mM)
X
DCN (5 mM)
R'OH (200 mM)
1a,c
(20 mM)
2A,B
(10 mM)
+
OR"
OR'
CH3CN
CO2Me
R"O
8-11
CN
CN
O
OR"
OR"
11O
R"O
R"O
11
OR'
OMe
OMe
8aA (88%)
R'=Et, 10aA (48%)
R'=i-Pr, 11aA (12%)
9aB (55%)
9cB
8cA
(83%)
(59%)
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Table 6. Formation of aldehyde 12 in the photoreaction of 1 and 2 with a low concentration of
water through the formation of intermediate 13.
8
9
ν
h , 5 h
X
X
BP (5 mM)
10
11
12
13
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15
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21
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DCN (5 mM)
H2O (200 mM)
H
1a,c
2A,B
+
OR"
OH
CO2Me
R"O
CH3CN
(20 mM) (10 mM)
R"O
O
12
13
CN
H
H
R"O
R"O
O
O
12aB (55%)
12cB
12aA (67%)
12cA
(46%)
(73%)
Scheme 2. Photoreactions of 1g,h with a low concentration of water.
ν
h , 5 h
BP (5 mM)
DCN (5 mM)
H2O (200 mM)
2A
+
CH3CN
(10 mM)
1g (20 mM)
CN
14 (19%)
ν
h , 5 h
BP (5 mM)
DCN (5 mM)
H2O (200 mM)
2A
3hA (73%)
+
CH3CN
(10 mM)
1h (20 mM)
Mechanistic insight into this process was obtained from deuterium incorporation and radical
trapping experiments (Scheme 3). The result of the photoinduced reaction of 1a and 2A in
CH3CN/D2O=9:1 showed that deuterated product dꢀ3aA was obtained with a high dꢀcontent
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(99%) and in similar yield (72%) to that with unꢀdeuterated water (Scheme 3a). This result
indicates that protonation occurs after carbanion formation at the αꢀcarbon attached to the cyano
group. TEMPO radical trapping was performed for the reaction of 1c and 2A in the presence of
2 equiv of TEMPO (40 mM) employing a long irradiation time (24 h) (Scheme 3b). Phen/DCB
as photocatalyst was used as the photocatalyst in this experiment because the high oxidation
ability of the excited state of DCN prevented TEMPO trapping. The formation of the
corresponding adduct 3cA was disturbed by the addition of TEMPO, and the TEMPO coupling
product was detected by FABꢀMass spectrometry (see Experimental section and Figure S2 (1H
NMR spectrum of crude product) in SI). The TEMPO product was not isolated because the
TEMPO coupling product was unstable for isolation. The corresponding TEMPO coupling
product produced under the photochemical conditions used the 2:1 adduct formation was also
detected by FABꢀMass spectrometry (see Experimental section and Figure S3 (1H NMR
spectrum of crude product) in SI). Addition of the radical trapping reagent tꢀdodecanethiol
(R”’SH, 0.2 mM) into aqueous acetonitrile solution of 1a and 2A catalyzed by Phen and DCB
provided reduction product 15 in 52% yield after extended irradiation (20 h). These results show
that the radical at the αꢀcarbon attached to the ether oxygen is generated after the nucleophilic
addition.
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Scheme 3. Deuterium incorporation, TEMPO trapping, and thiol trapping experiments in the
photoreaction of 1 and 2.
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9
a. Deuterium incorporation
ν
CN
h , 5 h
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BP (5 mM)
D
DCN (5 mM)
2A
1a
(20 mM)
+
OH
(20 mM) CH3CN/D2O=9:1
11O
d-3aA
(72%)
d-content: 99%
b. TEMPO trapping
ν
h , 24 h
Phen (5 mM)
DCB (5 mM)
TEMPO (40 mM)
N
O
1c
2A
+
OH
O
(20 mM) (20 mM) CH3CN/H2O=9:1
detected by FAB-Mass
ν
h , 24 h
Phen (5 mM)
DCB (5 mM)
MeOH (200 mM)
TEMPO (40 mM)
N
O
1c
2A
+
O
CH3CN
(20 mM) (10 mM)
O
OMe
detected by FAB-Mass
c. Hydrogen abstraction from thiol
ν
h , 20 h
Phen (5 mM)
DCB (5 mM)
H
R"'SH (0.2 mM)
2A
OH
11O
1a
(20 mM)
+
(20 mM) CH3CN/H2O=9:1
15 (52%)
Additional information about the photoreaction mechanism was obtained by the fluorescence
quenching (Figure 1). The fluorescence of DCN in the aqueous acetonitrile solution was
efficiently quenched by both BP (Figure 1a) and vinyl ether 1a (Figure 1b). The rate constants
for fluorescence quenching (kq) by BP and 1a were calculated as 7.48 × 108 and 7.18 × 108
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M–1s–1, respectively, from the SternꢀVolmer plot I0/I = 1 + kqτ[Q] (I0: fluorescence intensity of
DCN at 386 nm, I: observed fluorescence intensity of DCN at 386 nm with BP or 1a, τ = 10.1
ns (fluorescence lifetime of DCN)9, [Q]: concentration of BP or 1a). The RehmꢀWeller
equation10 confirms that both PET process are exothermic, as indicated by the negative ꢀG
values (–31 and –17 kJmol–1, ꢀG = 96.49[E(D /D)–E(A/A )]–Es) that were calculated using
the reduction potential (E(A/A ): –1.28 V vs. SCE in acetonitrile)11 and excited singlet energy
(Es: 333 kJmol–1)11 of DCN and the oxidation potential of BP and 1a (E(D /D): +1.85 and
+1.99 V vs. SCE in acetonitrile)12. These results indicate that the PET from both BP and 1a to
the excited state of DCN occurs smoothly, and the rate of PET between BP and DCN is slightly
faster than that between 1a and DCN, because BP has a lower oxidation potential than 1a.
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a. Fluorescence quenching of DCN with BP b. Fluorescence quenching of DCN with 1a
=
0
4.9 x 10-3
9.5 x 10-3
14.0 x 10-3
18.2 x 10-3
22.2 x 10-3
26.1 x 10-3
29.8 x 10-3
33.3 x 10-3
M
M
M
M
M
M
M
M
M
BP
1a
=
0
4.9 x 10-3
9.5 x 10-3
14.0 x 10-3
18.2 x 10-3
22.2 x 10-3
26.1 x 10-3
29.8 x 10-3
33.3 x 10-3
M
M
M
M
M
M
M
M
M
Figure 1. Fluorescence quenching of DCN with BP (a) and 1a (b) excited at 310 nm in
aqueous acetonitrile solution (CH3CN/H2O=9:1).
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Based on the aforementioned results and the results from a similar threeꢀcomponent coupling
photoreaction reported by D. R. Arnold13 and K. Mizuno14, a plausible mechanism for the
photoinduced crossꢀcoupling reaction between 1 and 2 is shown in Scheme 4. First, PET
between BP and the excited state of DCN by light absorption (>280 nm, see absorption spectra
of BP, DCN, and 1a (Figure S1 in SI)) generates the radical cation of BP and the radical anion
of DCN. Also, PET between 1 and the excited state of DCN generates the radical cation of 1 and
the radical anion of DCN (Scheme 4a). As shown in Entry 3 in Table 3, the efficiency of
photoreaction through the formation of the radical ion pair between 1 and DCN was quite low,
probably because back electron transfer (BET) was faster than nucleophilic attack to the radical
cation of 1. This means that the adducts are primarily obtained through the formation of the
BP/DCN radical ion pair as shown in Scheme 4b. A second electron transfer between 1 and the
radical cation of BP forms the radical cation of 1 and BP, even though it is estimated from the
oxidation potential of BP (+1.85 V)7 and 1 (e.g., 1b: +1.99 V)7 that the electron transfer is an
endothermic process. A similar electron transfer process between the radical cation of polycyclic
aromatic compounds such as BP and electronꢀrich alkenes such as 1b has been reported, and the
formation of a πꢀcomplex between the radical cation of BP and 1b was considered to promote
the electron transfer.15 However, the efficiency of the electron transfer between the radical
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cation of BP and alkenes having a high oxidation potential such as 1k,l,m is quite low and
therefore the adducts are not formed. Thus, BP serve as an electron mediator both to separate the
radical ion pair between 1 and DCN and to prevent fast BET in the photoreaction. When an
electronꢀrich alkene having a low oxidation potential (less than +2.62 V, for example 1j) is used
with a high concentration of the nucleophile R’OH, the high rate of nucleophilic addition to the
radical cation of 1 leads to the formation of the electronꢀrich radical 16, and subsequently
radical addition of 16 to 2A forms electronꢀdeficient radical 17. BET from the radical anion of
DCN to radical 17 generates the carbanion, as mentioned in the deuterium incorporation
experiment, followed by protonation to yield 1:1 adducts 3–7. However, when the concentration
of R’OH is low, the low rate of nucleophilic addition to the radical cation results in the
dimerization of vinyl ethers 1, as was reported in the similar PETꢀpromoted addition of vinyl
ethers to generate the radical cation of dimer 18.5g,16 Nucleophilic addition of R’OH to 18 forms
electronꢀrich radical 19, and the same radical and BET process provides 2:1 adducts 8–12.
When alkylꢀsubstituted alkenes 1g,h are employed in the place of vinyl ethers as the
electronꢀrich alkene in a low concentration of R’OH, the 2:1 adduct is not formed due to the low
rate of dimerization of the radical cations of 1g,h. In the case of 1g, substitution between the
radical cations of 1g and the radical anion of DCN takes place after decyanation to yield 14 as
previously reported.13b
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Scheme 4. Plausible mechanism for the photoreaction.
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a. First step
BP
DCN
DCN
+
BP
PET
ν
h
*
DCN
DCN
1
1
+
DCN
PET
1
+
BET
b. Pathway to adducts
*
ν
h
BP
DCN
RO
1
DCN
PET
e-
DCN
OR'
CN
BP
CN
RO
e-
BET
2A
H+
R'OH
1:1 adduct
RO
RO
OR'
RO
3-7
OR'
OR
16
RO
RO
17
e-
BET
R'OH
1
2A
H+
OR
2:1 adduct
8-12
OR'
18
19
Finally, the applicability of this process to the use of vinyl ethers from bioactive alcohols17 and
the conversion of the photoproducts to lactones18 was examined (Scheme 5). Vinyl ethers 1q–t
derived from bioactive alcohols such as Lꢀserine, Dꢀserine, Lꢀthreonine, and Dꢀborneol were
converted to diastereomeric mixture of crossꢀcoupling products 3qA–tA under the same
photochemical conditions as used previously (Scheme 5a). In addition, the hydrolysis of
photoproduct 3cA by NaOH and the sequential treatment by TFA led to the formation of
6ꢀmembered lactone 20, which is an intermediate for the preparation of an antineoplastic drug.19
Similarly, the hydrolysis of 3iA without TFA treatment provided the bicyclic lactone 21, which
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is an intermediate in the synthesis of an α2ꢀadrenoreceptor agonist.20
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Scheme 5. Photoreaction of vinyl ethers prepared from bioactive alcohols and conversion of the
photoproducts to lactones.
a. Preparation of vinyl ethers from bioactive alcohols and their photoreaction
ν
h , 5 h
BP (5 mM)
CN
Pd(OAc)2
phenanthroline
rt, 4 days
DCN (5 mM)
2A
(20 mM)
R
ROH
R
OH
O
CH3CN/H2O=9:1
O
DCM/EVE=3:5
1q-t (20 mM)
EVE: ethyl vinyl ether
CN
CN
BocHN
O
OH
BocHN
OH
O
CO2Me
CO2Me
3rA (76%)
dr=65:35
3qA (75%)
dr=66:34
CN
CN
H
O
BocHN
OH
O
OH
CO2Me
3tA (77%)
dr=50:50
3sA (79%)
dr=66:34
b. Modification of the photoproduct
CO2H
NaOH (3 M)
O
reflux, 2 days
TFA
3cA
MeOH/H2O
OH DCM
O
20 (60%)
O
HO
NaOH (3 M)
reflux, 2 days
3iA
MeOH/H2O
O
O
21 (99%)
dr=72:28
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Conclusion
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This study has led to the development of a new general method for the preparation of
crossꢀcoupling adducts between electronicallyꢀdifferentiated donor and acceptor alkenes
containing a nucleophile by using an organic photocatalyst (BP/DCN) under mild conditions.
This process can be employed with a variety of alkenes and alcohols as the substrates, and the
limitations of the alkenes were described. The selective formation of 1:1 or 2:1 adducts in the
photoreaction of vinyl ethers depends on the concentration of the nucleophile. The
photoinduced redox system using BP and DCN was found to be superior to the direct PET
process between 1 and DCN. Vinyl ethers are easily accessible from alcohols; therefore, this
method can be applied to the construction of the fundamental framework of complex molecules
from alcohols and alkenes. Further investigations for the application of this methodology to the
preparation of stereoselective adducts are underway.
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Experimental Section
General Information. All reagents and solvents were used as received from commercial
1
suppliers. IR spectra were recorded on an FTꢀIR spectrometer. H NMR spectra were recorded
in CDCl3 containing tetramethylsilane as an internal standard, and were acquired on either a 500
MHz spectrometer. 13C{1H} NMR spectra were acquired on a 125 MHz spectrometer.
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Highꢀresolution mass spectra were obtained using doubleꢀfocusing magnetic sector mass
spectrometer coupled with FAB. The light source was a highꢀpressure (100 W) mercury arcs
and blue LED (18 W, 405 nm). Column chromatography was performed on Wakogel Cꢀ300,
particle size 45ꢀ75 ꢁm.
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General procedure for the photoreaction of 1 with 2. An aqueous CH3CN solution (CH3CN
36 mL, H2O 4 mL) of 1 (20 mM), 2 (20 mM), BP (5 mM), and DCN (5 mM) in Pyrex vessels
(18 mm x 180 mm) was purged with Ar for 10 min. The mixture was irradiated with a 100 W
highꢀpressure mercury lamp for 5 h, and then the solvent was removed under reduced pressure.
The crude product was purified by silicaꢀgel column chromatography using hexane/EtOAc =
1:1 as the eluent to give adduct 3.
4-dodecyloxy-5-hydroxypentanenitrile (3aA): 0.164 g, 72%, white solid, mp 36–37 °C; IR (KBr,
cmꢀ1) 3437, 2923, 2854, 2248; 1H NMR (500 MHz, CDCl3) δ 3.77–3.74 (m, 1H), 3.61–3.44 (m,
4H), 2.51–2.44 (m, 2H), 2.24 (s (br), 1H), 1.94–1.84 (m, 2H), 1.60–1.55 (m, 2H), 1.38–1.14 (m,
18H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 119.7, 77.5, 70.3, 62.9, 31.9, 30.0,
29.7, 29.6, 29.5, 29.4, 27.3, 26.2, 22.7, 14.1, 13.4; HRMS (FAB, m/z) calcd for (M+H)+
C17H34NO2: 284.2590, found: 284.2607.
4-ethoxy-5-hydroxypentanenitrile (3bA): 0.075 g, 65%, colorless oil; IR (neat, cmꢀ1) 3435,
2976, 2934, 2879, 2248; 1H NMR (500 MHz, CDCl3) δ 3.74–3.64 (m, 2H), 3.57–3.46 (m, 3H),
2.54–2.40 (m, 3H), 1.93–1.863 (m, 2H), 1.23 (t, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
119.8, 77.4, 65.5, 63.0, 27.2, 15.5, 13.4; HRMS (FAB, m/z) calcd for (M+H)+ C7H14NO2:
144.1025, found: 144.1013.
4-tert-butoxy-5-hydroxypentanenitrile (3cA): 0.108 g, 79%, colorless oil; IR (neat, cmꢀ1) 3462,
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2978, 2881, 2248; H NMR (500 MHz, CDCl3) δ 3.73–3.69 (m, 1H), 3.59–3.50 (m, 2H),
2.49–2.42 (m, 3H), 2.28 (s (br), 1H), 1.92–1.87 (m, 2H), 1.26 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 120.1, 74.5, 69.3, 64.8, 28.9, 28.5, 13.3; HRMS (FAB, m/z) calcd for (M+H)+
C9H18NO2: 172.1338, found: 172.1322.
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3-(tetrahydro-2-hydroxy-pyran-3-yl)propanenitrile (3dA’): 0.078 g, 68%, colorless oil; IR (neat,
cmꢀ1) 3432, 2931, 2858, 2247; 1H NMR (500 MHz, CDCl3) δ 5.09 (s, 0.4H), 4.43 (t, J = 6.0 Hz,
0.6H), 4.02–3.93 (m, 1H), 3.83 (d, J = 6.0 Hz, 0.6H), 3.60–3.57 (m, 0.4H), 3.52–3.47 (m, 0.6H),
3.30 (s, 0.4H), 2.51–2.47 (m, 1.2H), 2.45–2.36 (m, 0.8H), 1.97–1.89 (m, 1.2H), 1.84–1.78 (m,
0.8H), 1.68–1.49 (m, 3H), 1.26–1.19 (m, 2H), 0.89–0.84 (m, 0.4H); 13C NMR (125 MHz,
CDCl3) δ 120.0, 119.8, 99.5, 93.0, 65.6, 60.0, 40.9, 38.4, 29.7, 27.7, 27.0, 24.7, 23.3, 15.4, 14.6;
HRMS (FAB, m/z) calcd for (M+H)+ C8H14NO2: 156.1025, found:156.1026.
3-(tetrahydro-3-hydroxy-pyran-2-yl)propanenitrile (3dA): 0.022 g, 13%, colorless oil; IR (neat,
cmꢀ1) 3439, 2940, 2853, 2247; 1H NMR (500 MHz, CDCl3) δ 4.01–3.98 (m, 1H), 3.65–3.63 (m,
1H), 3.51–3.43 (m, 2H), 2.50–2.47 (m, 2H), 2.07–1.86 (m, 4H), 1.79–1.69 (m, 2H), 1.47–1.43
(m, 1H); 13C NMR (125 MHz, CDCl3) δ 119.7, 77.6, 68.6, 66.7, 30.6, 27.8, 20.0, 13.6; HRMS
(FAB, m/z) calcd for (M+H)+ C8H14NO2: 156.1025, found: 156.1005.
5-hydroxy-4-(3-phenylpropoxy)pentanenitrile (3eA): 0.121 g, 65%, colorless oil; IR (neat,
1
cmꢀ1) 3441, 3060, 3026, 2940, 2247; H NMR (500 MHz, CDCl3) δ 7.31–7.18 (m, 5H),
3.76–3.73 (m, 1H), 3.63–3.58 (m, 1H), 3.53–3.45 (m, 3H), 2.72–2.69 (m, 2H), 2.52–2.41 (m,
2H), 1.96–1.79 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 141.5, 128.41, 128.37, 126.0, 119.7,
77.5, 69.2, 62.9, 32.33, 31.4, 27.2, 13.4; HRMS (FAB, m/z) calcd for (M+H)+ C14H20NO2:
234.1494, found: 234.1492.
5-hydroxy-4-(2-hydroxyethoxy)pentanenitrile (3fA): 0.083 g, 65%, colorless oil; IR (neat, cmꢀ1)
3424, 2937, 2876, 2248; 1H NMR (500 MHz, CDCl3) δ 3.84–3.70 (m, 5H), 3.60–3.54 (m, 2H),
3.02 (s (br), 1H), 2.85 (s (br), 1H), 2.58–2.44 (m, 2H), 1.97–1.81 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 119.8, 78.7, 71.4, 63.4, 62.2, 27.2, 13.6; HRMS (FAB, m/z) calcd for (M+H)+
C7H14NO3: 160.0974, found:160.0968.
5-hydroxy-4,4,5-trimethylhexanenitrile (3gA): 0.092 g, 74%, colorless oil; IR (neat, cmꢀ1) 3438,
2970, 2881, 2246; 1H NMR (500 MHz, CDCl3) δ 2.43–2.40 (m, 2H), 1.82–1.78 (m, 2H), 1.42 (s
(br), 1H), 1.21 (s, 6H), 0.93 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 121.0, 75.3, 39.6, 33.6, 25.7,
21.7, 13.3; HRMS (FAB, m/z) calcd for (M+H)+ C9H18NO: 156.1389, found: 156.1375.
5-hydroxy-4,4-dimethylhexanenitrile (3hA): 0.081 g, 72%, colorless oil; IR (neat, cmꢀ1) 3456,
2973, 2248; 1H NMR (500 MHz, CDCl3) δ 3.52 (q, J = 6.4 Hz, 1H), 2.43–2.31 (m, 2H), 2.02 (s
(br), 1H), 1.84–1.78 (m, 1H), 1.66–1.60 (m, 1H), 1.14 (d, J = 6.4 Hz, 3H), 0.92–0.85 (s, 6H);
13C NMR (125 MHz, CDCl3) δ 120.8, 73.6, 37.2, 34.3, 22.9, 21.8, 18.0, 12.5; HRMS (FAB,
m/z) calcd for (M+H)+ C8H16NO: 142.1232, found: 142.1227.
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3-(2-hydroxycyclohexyl)propanenitrile (3iA): 0.085 g, 69%, colorless oil; IR (neat, cmꢀ1) 3435,
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2929, 2858, 2248; H NMR (500 MHz, CDCl3) δ 3.92–3.90 (m, 0.1H), 3.24–3.22 (m, 0.9H),
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2.55–2.40 (m, 2H), 2.16–2.09 (m, 0.9H), 1.99–1.95 (m, 0.9H), 1.83–1.16 (m, 9.3H), 1.00–0.92
(m, 0.9H); 13C NMR (125 MHz, CDCl3) δ 120.4, 74.8, 68.3, 44.1, 39.9, 36.2, 33.1, 30.3, 29.0,
27.5, 26.1, 25.3, 24.7, 20.2, 15.2, 14.8; HRMS (FAB, m/z) calcd for (M+H)+ C9H16NO:
154.1232, found:154.1252.
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3-(1-(hydroxymethyl)cyclohexyl)propanenitrile (3jA): 0.043 g, 32%, colorless oil; IR (neat,
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cmꢀ1) 3443, 2876, 2249; H NMR (500 MHz, CDCl3) δ 3.46 (s, 2H), 2.36 (t, J = 8.0 Hz, 2H),
1.79 (t, J = 8.0 Hz, 2H), 1.67 (s (br), 1H), 1.51–1.26 (m, 10H); 13C NMR (125 MHz, CDCl3) δ
120.9, 67.7, 36.9, 32.2, 31.4, 26.1, 21.3, 11.8; HRMS (FAB, m/z) calcd for (M+H)+ C10H18NO:
168.1389, found: 168.1376.
4-ethylthio-5-hydroxypentanenitrile (3nA): 0.011 g, 9%, colorless oil; IR (neat, cmꢀ1) 3436,
2932, 2248; 1H NMR (500 MHz, CDCl3) δ 3.70–3.67 (m, 1H), 3.65–3.61 (m, 1H), 2.89–2.83 (m,
1H), 2.65–2.55 (m, 4H), 2.30–2.26 (m, 1H), 2.09–2.02 (m, 1H), 1.81–1.74 (m, 1H), 1.29 (t, J =
7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 119.4, 64.1, 47.4, 27.5, 25.0, 15.1; HRMS (FAB,
m/z) calcd for (M+H)+ C7H14NOS: 160.0796, found: 160.0774.
methyl 4-dodecyloxy-5-hydroxypentanoate (3aB): 0.117 g, 46%, colorless oil; IR (neat, cmꢀ1)
3460, 2925, 2858, 1741; 1H NMR (500 MHz, CDCl3) δ 3.68–3.65 (m, 4H), 3.52–3.46 (m, 3H),
3.40–3.38 (m, 1H), 2.41 (t, J = 7.5 Hz, 2H), 2.10 (s (br), 1H), 1.91–1.81 (m, 2H), 1.59–1.53 (m,
2H), 1.38–1.14 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 174.1, 78.6,
69.9, 63.7, 51.7, 31.9, 30.1, 29.67, 29.65, 29.63, 29.5, 29.4, 26.2, 26.0, 22.7, 14.1; HRMS (FAB,
m/z) calcd for (M+H)+ C18H37O4: 317.2692, found: 317.2680.
methyl 4-tert-butoxy-5-hydroxypentanoate (3cB): 0.082 g, 50%, colorless oil; IR (neat, cmꢀ1)
3466, 2974, 2824, 1739; 1H NMR (500 MHz, CDCl3) δ 3.68–3.66 (m, 4H), 3.57–3.54 (m, 1H),
3.46–3.44 (m, 1H), 2.39 (t, J = 7.5 Hz, 2H), 2.07 (s (br), 1H), 1.89–1.83 (m, 2H), 1.24 (s, 9H);
13C NMR (125 MHz, CDCl3) δ 174.3, 74.2, 69.9, 64.9, 51.6, 29.6, 28.6, 28.0; HRMS (FAB,
m/z) calcd for (M+H)+ C10H21O4: 205.1440, found: 205.1423.
ethyl 4-dodecyloxy-5-hydroxypentanoate (3aC): 0.124 g, 46%, colorless oil; IR (neat, cmꢀ1)
3457, 2927, 2849, 1738; 1H NMR (500 MHz, CDCl3) δ 4.13 (q, J = 7.2 Hz, 2H), 3.66–3.64 (m,
1H), 3.52–3.47 (m, 3H), 3.41–3.37 (m, 1H), 2.39 (t, J = 7.5 Hz, 2H), 2.28 (s (br), 1H),
1.90–1.81 (m, 2H), 1.57–1.53 (m, 2H), 1.38–1.14 (m, 21H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 173.7, 78.7, 69.9, 63.7, 60.4, 31.9, 30.1, 30.0, 29.69, 29.65, 29.52, 29.4,
26.2, 26.0, 22.7, 14.2, 14.1; HRMS (FAB, m/z) calcd for (M+H)+ C19H39O4: 331.2848, found:
331.2846.
ethyl 4-tert-butoxy-5-hydroxypentanoate (3cC): 0.087 g, 50%, colorless oil; IR (neat, cmꢀ1)
3466, 2972, 2876, 1732; 1H NMR (500 MHz, CDCl3) δ 4.13 (q, J = 7.0 Hz, 2H), 3.68–3.66 (m,
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1H), 3.58–3.54 (m, 1H), 3.47–3.43 (m, 1H), 2.37 (t, J = 7.5 Hz, 2H), 2.08 (s (br), 1H),
1.88–1.82 (m, 2H), 1.27–1.18 (m, 12H); 13C NMR (125 MHz, CDCl3) δ 173.9, 74.2, 70.0, 64.9,
60.4, 29.9, 28.6, 28.0, 14.2; HRMS (FAB, m/z) calcd for (M+H)+ C11H23O4: 219.1596, found:
219.1602.
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tert-butyl 4-dodecyloxy-5-hydroxypentanoate (3aD): 0.133 g, 47%, colorless oil; IR (neat,
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cmꢀ1) 3311, 3080, 2928, 2858, 1731; H NMR (500 MHz, CDCl3) δ 3.65–3.62 (m, 1H),
3.59–3.47 (m, 3H), 3.40–3.37 (m, 1H), 2.30 (t, J = 7.3 Hz, 2H), 2.24 (s (br), 1H), 1.86–1.75 (m,
2H), 1.59–1.54 (m, 2H), 1.45 (s, 9H), 1.38–1.14 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 173.0, 80.4, 78.8, 69.9, 63.8, 31.9, 31.0, 30.1, 29.7, 29.6, 29.5, 29.4, 28.1,
26.2, 26.0, 22.7, 14.1; HRMS (FAB, m/z) calcd for (M+H)+ C21H43O4: 359.3162, found:
359.3140.
tert-butyl 4-tert-butoxy-5-hydroxypentanoate (3cD): 0.101 g, 51%, colorless oil; IR (neat, cmꢀ1)
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3462, 2964, 1730; H NMR (500 MHz, CDCl3) δ 3.67–3.65 (m, 1H), 3.56–3.53 (m, 1H),
3.45–3.43 (m, 1H), 2.29 (t, J = 7.5 Hz, 2H), 2.15 (s (br), 1H), 1.84–1.77 (m, 2H), 1.45 (s, 9H),
1.21 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 173.3, 80.4, 74.1, 70.1, 65.0, 31.0, 28.6, 28.11,
28.06; HRMS (FAB, m/z) calcd for (M+H)+ C13H27O4: 247.1909, found: 247.1919.
4-dodecyloxy-5-hydroxypentanoic acid (3aE): 0.082 g, 34%, white solid, mp 33–35 °C; IR
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(KBr, cmꢀ1) 3402, 2925, 2854, 1739; H NMR (500 MHz, CDCl3) δ 3.71–3.68 (m, 1H),
3.53–3.41 (m, 4H), 2.46 (t, J = 7.5 Hz, 2H), 1.93–1.83 (m, 2H), 1.58–1.54 (m, 2H), 1.38–1.14
(m, 18H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 178.3, 78.6, 70.1, 63.6, 31.9,
30.1, 29.67, 29.65, 29.60, 29.5, 29.4, 26.2, 25.8, 22.7, 14.1; HRMS (FAB, m/z) calcd for
(M+H)+ C17H35O4: 303.2535, found: 303.2541.
4-dodecyloxy-5-hydroxypentanamide (3aF): 0.123 g, 51%, white solid, mp 67–68 °C; IR (KBr,
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cmꢀ1) 3394, 2955, 2923, 2853, 1662, 1615; H NMR (500 MHz, CDCl3) δ 5.79 (s (br), 2H),
3.66–3.63 (m, 1H), 3.53–3.40 (m, 4H), 2.56 (s (br), 1H), 2.37–2.28 (m, 2H), 1.92–1.86 (m, 2H),
1.57–1.53 (m, 2H), 1.38–1.14 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
175.6, 78.8, 69.8, 63.3, 31.9, 31.1, 30.1, 29.67, 29.65, 29.5, 29.4, 26.2, 26.1, 22.7, 14.1; HRMS
(FAB, m/z) calcd for (M+H)+ C17H36NO3: 302.2695, found: 302.2695.
N-tert-butyl-4-dodecyloxy-5-hydroxypentanamide (3aG): 0.139 g, 48%, colorless oil; IR (neat,
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cmꢀ1) 3311, 3080, 2928, 2858, 1646, 1552; H NMR (500 MHz, CDCl3) δ 5.43 (s (br), 1H),
3.61–3.59 (m, 1H), 3.51–3.47 (m, 3H), 3.41–3.38 (m, 1H), 2.59 (s (br), 1H), 2.23–2.14 (m, 2H),
1.92–1.82 (m, 2H), 1.59–1.53 (m, 2H), 1.39–1.21 (m, 27H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 172.3, 78.8, 69.7, 63.3, 51.2, 32.4, 31.9, 30.1, 29.7, 29.6, 29.5, 29.4, 28.8,
26.2, 25.9, 22.7, 14.1; HRMS (FAB, m/z) calcd for (M+H)+ C21H44NO3: 358.3321, found:
358.3326.
4-dodecyloxy-5-hydroxy-3-methylpentanenitrile (3aH): 0.048 g, 20%, colorless oil; IR (neat,
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cmꢀ1) 3449, 2921, 2858, 2248; 1H NMR (500 MHz, CDCl3) δ 3.86–3.83 (m, 1H), 3.64–3.56 (m,
2H), 3.45–3.40 (m, 1H), 3.14–3.11 (m, 1H), 2.57–2.46 (m, 2H), 2.22–2.16 (m, 1H), 1.83 (s (br),
1H), 1.62–1.56 (m, 2H), 1.38–1.14 (m, 18H), 1.12 (d, J = 6.5 Hz, 3H), 0.88 (t, J = 7.0 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 118.9, 82.0, 70.7, 60.2, 31.9, 31.5, 30.1, 29.7, 29.64, 29.62,
29.60, 29.5, 29.4, 26.2, 22.7, 21.1, 16.1, 14.1; HRMS (FAB, m/z) calcd for (M+H)+ C18H36NO2:
298.2746, found: 298.2754.
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4-tert-butoxy-5-hydroxy-3-methylpentanenitrile (3cH): 0.032 g, 21%, colorless oil; IR (neat,
cmꢀ1) 3484, 3008, 2865, 2247; 1H NMR (500 MHz, CDCl3) δ 3.70–3.43 (m, 3H), 2.65–2.50 (m,
1H), 2.43–2.27 (m, 1H), 2.18–2.15 (m, 1H), 1.94–1.92 (m, 1H), 1.28–1.22 (m, 9H), 1.12 (t, J =
7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 119.7, 119.4, 74.6, 73.5, 72.5, 62.7, 62.1, 34.6, 32.5,
28.8, 28.6, 21.2, 20.3, 16.2, 15.8; HRMS (FAB, m/z) calcd for (M+H)+ C10H20NO2: 186.1494,
found:186.1487.
4-dodecyloxy-5-methoxypentanenitrile (4aA): 0.181 g, 76%, colorless oil; IR (neat, cmꢀ1) 2926,
2854, 2247; 1H NMR (500 MHz, CDCl3) δ 3.65–3.61 (m, 1H), 3.51–3.33 (m, 7H), 2.50–2.46 (m,
2H), 1.92–1.84 (m, 2H), 1.60–1.53 (m, 2H), 1.38–1.14 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 119.8, 76.1, 73.7, 70.5, 59.3, 31.9, 30.0, 29.7, 29.6, 29.5, 29.4, 28.0,
26.1, 22.7, 14.1, 13.4; HRMS (FAB, m/z) calcd for (M+H)+ C18H36NO2: 298.2746, found:
298.2754.
4-tert-butoxy-5-methoxypentanenitrile (4cA): 0.116 g, 78%, colorless oil; IR (neat, cmꢀ1) 2976,
2933, 2247; 1H NMR (500 MHz, CDCl3) δ 3.74–3.72 (m, 1H), 3.41–3.35 (m, 4H), 3.26–3.23 (m,
1H), 2.45–2.42 (m, 2H), 1.95–1.92 (m, 1H), 1.85–1.82 (m, 1H), 1.23 (s, 9H); 13C NMR (125
MHz, CDCl3) δ 120.3, 75.5, 74.3, 67.8, 59.2, 29.5, 28.4, 13.0; HRMS (FAB, m/z) calcd for
(M+H)+ C10H20NO2: 186.1494, found: 186.1477.
4-dodecyloxy-5-ethoxypentanenitrile (5aA): 0.180 g, 72%, colorless oil; IR (neat, cmꢀ1) 2928,
2855, 2247; 1H NMR (500 MHz, CDCl3) δ 3.66–3.61 (m, 1H), 3.53–3.47 (m, 4H), 3.44–3.40 (m,
2H), 2.50–2.46 (m, 2H), 1.94–1.75 (m, 2H), 1.60–1.53 (m, 2H), 1.38–1.14 (m, 21H), 0.88 (t, J =
6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 119.9, 76.3, 71.6, 70.5, 66.9, 31.9, 30.1, 29.7, 29.6,
29.5, 29.4, 28.2, 26.1, 22.7, 15.1, 14.1, 13.4; HRMS (FAB, m/z) calcd for (M+H)+
C19H38NO2:312.2902, found: 312.2888.
4-tert-butoxy-5-ethoxypentanenitrile (5cA): 0.065 g, 41%, colorless oil; IR (neat, cmꢀ1) 2976,
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2934, 2871, 2246; H NMR (500 MHz, CDCl3) δ 3.74–3.72 (m, 1H), 3.51–3.43 (m, 3H),
3.27–3.24 (m, 1H), 2.44 (t, J = 7.3 Hz, 2H), 1.98–1.94 (m, 1H), 1.85–1.80 (m, 1H), 1.29–1.17
(m, 12H); 13C NMR (125 MHz, CDCl3) δ 120.3, 74.3, 73.3, 68.0, 66.8, 29.7, 28.4, 15.1, 13.0;
HRMS (FAB, m/z) calcd for (M+H)+ C11H22NO2: 200.1650, found: 200.1672.
4-dodecyloxy-5-isopropoxypentanenitrile (6aA): 0.175 g, 67%, colorless oil; IR (neat, cmꢀ1)
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2927, 2858, 2251; H NMR (500 MHz, CDCl3) δ 3.66–3.54 (m, 2H), 3.49–3.37 (m, 4H),
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2.49–2.46 (m, 2H), 1.95–1.90 (m, 1H), 1.84–1.79 (m, 1H), 1.59–1.52 (m, 2H), 1.32–1.21 (m,
18H), 1.14 (d, J = 5.8 Hz, 6H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 120.0,
76.5, 72.2, 70.5, 69.3, 31.9, 30.1, 29.7, 29.6, 29.5, 29.4, 28.3, 26.1, 22.7, 22.1, 22.0, 14.1, 13.4;
HRMS (FAB, m/z) calcd for (M+H)+ C20H40NO2: 326.3060, found: 326.3062.
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4-tert-butoxy-5-isopropoxypentanenitrile (6cA): 0.052 g, 30%, colorless oil; IR (neat, cmꢀ1)
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2974, 2927, 2247; H NMR (500 MHz, CDCl3) δ 3.71–3.68 (m, 1H), 3.56–3.54 (m, 1H),
3.45–3.42 (m, 1H), 3.22–3.19 (m, 1H), 2.43 (t, J = 7.5 Hz, 2H), 1.99–1.95 (m, 1H), 1.83–1.79
(m, 1H), 1.20 (s, 9H), 1.15 (d, J = 6.0 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 120.4, 74.2, 72.1,
70.9, 68.3, 29.8, 28.5, 22.1, 22.0, 13.0; HRMS (FAB, m/z) calcd for (M+H)+ C12H24NO2:
214.1807, found: 214.1793.
5-tert-butoxy-4-dodecyloxypentanenitrile (7aA): 0.158 g, 58%, colorless oil; IR (neat, cmꢀ1)
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2925, 2885, 2246; H NMR (500 MHz, CDCl3) δ 3.66–3.61 (m, 1H), 3.46–3.40 (m, 3H),
3.28–3.25 (m, 1H), 2.47 (t, J = 7.5 Hz, 2H), 1.97–1.92 (m, 1H), 1.81–1.76 (m, 1H), 1.59–1.50
(m, 2H), 1.30–1.21 (m, 18H), 1.17 (s, 9H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 120.0, 76.9, 73.1, 70.6, 63.0, 31.9, 30.1, 29.7, 29.6, 29.5, 29.4, 28.4, 27.4, 26.2, 22.7,
14.1, 13.4; HRMS (FAB, m/z) calcd for (M+H)+ C21H42NO2: 340.3216, found: 340.3224.
4,5-di-tert-butoxypentanenitrile (7cA): 0.039 g, 22%, colorless oil; IR (neat, cmꢀ1) 2974, 2247;
1H NMR (500 MHz, CDCl3) δ 3.66–3.63 (m, 1H), 3.38–3.36 (m, 1H), 3.13–3.10 (m, 1H), 2.43
(t, J = 7.5 Hz, 2H), 2.00–1.96 (m, 1H), 1.82–1.77 (m, 1H), 1.21 (s, 9H), 1.17 (s, 9H); 13C NMR
(125 MHz, CDCl3) δ 120.5, 74.1, 72.9, 68.7, 64.6, 29.8, 28.5, 27.5, 13.0; HRMS (FAB, m/z)
calcd for (M+H)+ C13H26NO2: 228.1964, found: 228.1973.
4,7-didodecyloxy-7-methoxyheptanenitrile (8aA): 0.179 g, 88%, colorless oil; IR (neat, cmꢀ1)
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2925, 2853, 2246; H NMR (500 MHz, CDCl3) δ 4.41–4.40 (m, 1H), 3.59–3.29 (m, 8H),
2.48–2.42 (m, 2H), 1.85–1.50 (m, 10H), 1.38–1.14 (m, 36H), 0.88 (t, J = 6.8 Hz, 6H); 13C NMR
(125 MHz, CDCl3) δ 119.9, 103.7, 103.6, 69.4, 66.0, 52.7, 31.9, 30.1, 29.8, 29.6, 29.5, 29.3,
28.4, 28.2, 26.2, 22.7, 14.1, 13.3; HRMS (FAB, m/z) calcd for (M+H)+ C32H64NO3: 510.4886,
found: 510.4862.
4,7-di-tert-butoxy-7-methoxyheptanenitrile (8cA): 0.094 g, 83%, colorless oil; IR (neat, cmꢀ1)
2974, 2827, 2246; 1H NMR (500 MHz, CDCl3) δ 4.66–4.64 (m, 1H), 3.64–3.62 (m, 1H), 3.23 (s,
3H), 2.45–2.37 (m, 2H), 1.83–1.72 (m, 2H), 1.61–1.47 (m, 4H), 1.21 (s, 9H), 1.17 (s, 9H); 13C
NMR (125 MHz, CDCl3) δ 120.20, 120.18, 97.4, 97.3, 73.8, 73.7, 68.8, 68.7, 50.1, 50.0, 31.3,
31.1, 30.7, 29.8, 29.7, 28.7, 28.6, 13.1, 13.0; HRMS (FAB, m/z) calcd for (M+H)+ C16H32NO3:
286.2382, found: 286.2382.
methyl 4,7-didodecyloxy-7-methoxyheptanoate (9aB): 0.119 g, 55%, colorless oil; IR (neat,
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cmꢀ1) 2909, 2840, 1739; H NMR (500 MHz, CDCl3) δ 4.42–4.39 (m, 1H), 3.67 (s, 3H),
3.58–3.54 (m, 1H), 3.43–3.25 (m, 7H), 2.41–2.37 (m, 2H), 1.85–1.46 (m, 10H), 1.38–1.14 (m,
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36H), 0.88 (t, J = 6.8 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 174.3, 103.8, 77.9, 69.2, 66.0,
65.9, 52.7, 52.6, 51.5, 31.9, 30.2, 30.0, 29.9, 29.69, 29.65, 29.55, 29.51, 29.4, 29.1, 28.7, 26.31,
26.27, 22.7, 14.1; HRMS (FAB, m/z) calcd for (M+H–OMe)+ C32H64O4: 512.4804, found:
512.4796.
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methyl 4,7-di-tert-butoxy-7-methoxyheptanoate (9cB): 0.075 g, 59%, colorless oil; IR (neat,
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cmꢀ1) 2947, 2802, 1740; H NMR (500 MHz, CDCl3) δ 4.66–4.64 (m, 1H), 3.67 (s, 3H),
3.55–3.53 (m, 1H), 3.23 (s, 3H), 2.39–2.36 (m, 2H), 1.84–1.45 (m, 6H), 1.23 (s, 9H), 1.18 (s,
9H); 13C NMR (125 MHz, CDCl3) δ 174.4, 97.6, 97.4, 73.7, 73.3, 69.7, 69.5, 51.4, 49.83, 49.77,
31.00, 30.95, 30.8, 30.5, 30.0, 29.9, 29.8, 28.7, 28.6; HRMS (FAB, m/z) calcd for (M+H)+
C17H35O5: 319.2484, found: 319.2465.
4,7-didodecyloxy-7-ethoxyheptanenitrile (10aA): 0.101 g, 48%, colorless oil; IR (neat, cmꢀ1)
2889, 2247; 1H NMR (500 MHz, CDCl3) δ 4.47–4.45 (m, 1H), 3.66–3.35 (m, 7H), 2.46–2.42 (m,
2H), 1.83–1.52 (m, 10H), 1.32–1.19 (m, 39H), 0.88 (t, J = 6.8 Hz, 6H); 13C NMR (125 MHz,
CDCl3) δ 119.9, 102.8, 69.5, 65.8, 61.22, 61.17, 31.9, 30.1, 29.9, 29.69, 29.65, 29.5, 29.4, 29.0,
28.3, 26.30, 26.27, 22.7, 15.3, 14.1, 13.4; HRMS (FAB, m/z) calcd for (M+H)+ C33H66NO3:
524.5042, found: 524.5043.
4,7-didodecyloxy-7-isopropoxyheptanenitrile (11aA): 0.026 g, 12%, colorless oil; IR (neat,
cmꢀ1) 2923, 2615, 2246; 1H NMR (500 MHz, CDCl3) δ 4.53–4.51 (m, 1H), 3.88–3.84 (m, 1H),
3.54–3.49 (m, 2H), 3.43–3.36 (m, 3H), 2.46–2.43 (m, 2H), 1.86–1.55 (m, 10H), 1.26–1.13 (m,
42H), 0.88 (t, J = 6.8 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 119.9, 101.3, 76.9, 69.5, 68.61,
68.55, 64.7, 31.9, 30.1, 29.9, 29.68, 29.65, 29.5, 29.4, 28.42, 28.35, 26.32, 26.27, 23.3, 22.7,
22.3, 14.1, 13.4; HRMS (FAB, m/z) calcd for (M+H–OiPr)+ C31H61NO2: 479.4702, found:
479.4677.
4-dodecyloxy-6-formylhexanenitrile (12aA): 0.166 g, 67%, colorless oil; IR (neat, cmꢀ1) 2926,
2858, 2247, 1713; 1H NMR (500 MHz, CDCl3) δ 9.78 (s, 1H), 3.46–3.36 (m, 3H), 2.53–2.43 (m,
4H), 1.90–1.76 (m, 4H), 1.56–1.51 (m, 2H), 1.38–1.14 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 201.6, 119.7, 76.1, 69.7, 39.4, 31.9, 30.0, 29.70, 29.66, 29.64, 29.62,
29.60, 29.5, 29.4, 26.2, 25.6, 22.7, 14.1, 13.2; HRMS (FAB, m/z) calcd for (M+H)+ C19H36NO2:
310.2746, found: 310.2753.
4-tert-butoxy-6-formylhexanenitrile (12cA): 0.058 g, 73%, colorless oil; IR (neat, cmꢀ1) 2975,
2821, 2246, 1725; 1H NMR (500 MHz, CDCl3) δ 9.79 (s, 1H), 3.72–3.70 (m, 1H), 2.57–2.36 (m,
4H), 1.88–1.71 (m, 4H), 1.22 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 201.9, 119.9, 74.2, 67.8,
39.3, 31.2, 28.6, 27.6, 13.0; HRMS (FAB, m/z) calcd for (M+H)+ C11H20NO2: 198.1494, found:
198.1513.
methyl 4-dodecyloxy-6-formylhexanoate (12aB): 0.075 g, 55%, colorless oil; IR (neat, cmꢀ1)
2985, 2804, 2718, 1740, 1715; 1H NMR (500 MHz, CDCl3) δ 9.77 (s, 1H), 3.68–3.62 (m, 4H),
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3.41–3.29 (m, 2H), 2.51 (t, J = 7.0 Hz, 2H), 2.39 (t, J = 7.3 Hz, 2H), 1.85–1.76 (m, 4H),
1.58–1.48 (m, 2H), 1.38–1.17 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
202.2, 174.0, 77.2, 69.3, 63.0, 51.6, 39.8, 32.7, 31.9, 30.0, 29.7, 29.61, 29.58, 29.44, 29.39,
29.31, 28.8, 26.2, 25.7, 22.6, 14.1; HRMS (FAB, m/z) calcd for (M+H)+ C20H39O4: 343.2849,
found: 343.2854.
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methyl 4-tert-butoxy-6-formylhexanoate (12cB): 0.042 g, 46%, colorless oil; IR (neat, cmꢀ1)
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2975, 2723, 1734, 1714; H NMR (500 MHz, CDCl3) δ 9.78 (s, 1H), 3.68–3.61 (m, 4H),
2.53–2.36 (m, 4H), 1.82–1.71 (m, 4H), 1.20 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 202.6,
174.2, 73.8, 68.7, 51.6, 39.7, 30.7, 29.8, 28.6, 28.5, 28.0; HRMS (FAB, m/z) calcd for (M+H)+
C12H23O4: 231.1596, found: 231.1603.
1-cyano-4-(1,1,2-trimethylprop-2-enyl)naphthalene (14): 0.005 g, 19%, colorless oil; IR (neat,
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cmꢀ1) 2985, 2915, 2213, 1583, 1509; H NMR (500 MHz, CDCl3) δ 8.27 (d, J = 8.0 Hz, 1H),
8.14 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.71–7.63 (m, 2H), 7.29 (d, J = 7.5 Hz, 1H),
3.88 (s, 2H), 1.82 (s, 3H), 1.75 (s, 3H), 1.62 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 143.1,
132.6, 132.5, 132.3, 128.1, 128.0, 127.3, 126.0, 124.3, 124.2, 118.3, 108.4, 37.4, 20.7, 20.6,
18.8; HRMS (FAB, m/z) calcd for (M+H)+ C17H18N: 236.1440, found:236.1438.
Procedure for the TEMPO trapping of the photoreactions of 1c and 2A in high and low
concentrations of water and MeOH. An aqueous CH3CN solution (CH3CN 18 mL, H2O 2
mL) of 1c (20 mM), 2A (20 mM), Phen (5 mM), DCB (5 mM), and TEMPO (40 mM) in a
Pyrex vessel (18 mm x 180 mm) was purged with Ar for 10 min. The mixture was irradiated
with a 100 W highꢀpressure mercury lamp for 24 h, and then the solvent was removed without
heating by blowing with air. The crude product (1:1 adduct with TEMPO) was measured by 1H
NMR (Figure S2 in SI) and FABꢀMass spectrometry. The photoreaction of 1c (20 mM), 2A (10
mM), Phen (5 mM), DCB (5 mM), and TEMPO (40 mM) in a low concentration of MeOH (200
mM) was carried out in a similar manner to detect 2:1 adduct with TEMPO by 1H NMR (Figure
S3 in SI) and FABꢀMass spectrometry. 1:1 adduct with TEMPO: HRMS (FAB, m/z) calcd for
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(M+H)+ C15H32NO3: 274.2382, found: 274.2404. 2:1 adduct with TEMPO: HRMS (FAB, m/z)
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calcd for (M+H)+ C22H46NO4: 388.3427, found: 388.3412.
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[2-D]-4-dodecyloxy-5-hydroxypentanenitrile (d-3aA): 0.164 g, 72%, white solid, mp 36–37 °C;
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IR (KBr, cmꢀ1) 3435, 2922, 2854, 2249; H NMR (500 MHz, CDCl3) δ 3.77–3.74 (m, 1H),
3.61–3.44 (m, 4H), 2.49–2.45 (m, 1H), 2.04–1.83 (m, 3H), 1.61–1.55 (m, 2H), 1.38–1.14 (m,
18H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 119.7, 77.5, 70.3, 63.0, 31.9, 30.1,
29.66, 29.65, 29.62, 29.5, 29.4, 27.2, 26.2, 22.7, 14.1, 13.2 (t, J = 20.3 Hz); HRMS (FAB, m/z)
calcd for (M+H)+ C17H33DNO2: 285.2652, found: 285.2653.
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2-dodecyloxyethanol (15): 0.096 g, 52%, colorless oil; IR (neat, cmꢀ1) 3467, 2896; H NMR
(500 MHz, CDCl3) δ 3.74–3.72 (m, 2H), 3.54 (t, J = 4.5 Hz, 2H), 3.47 (t, J = 6.8 Hz, 2H), 2.06
(s (br), 1H), 1.60–1.56 (m, 2H), 1.38–1.14 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 71.7, 71.4, 61.9, 31.9, 29.64, 29.59, 29.47, 29.3, 26.1, 22.7, 14.1; HRMS (FAB,
m/z) calcd for (M+H)+ C14H31O2: 231.2324, found:231.2319.
Procedure for the preparation of vinyl ethers 1q–t from alcohols. Ethyl vinyl ether/CH2Cl2
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5:3 (25:15 mL) solution containing Pd(II) acetate (0.05 g, 0.22 mmol) and
1,10ꢀphenanthroline (0.04 g, 0.22 mmol) was stirred for 15 min. (S)-NꢀBoc Ser(OH)OMe (1.62
g, 7.4 mmol) was added, and the solution was stirred for 4 d at room temperature. The mixture
was filtered through celite, and the filtrate was evaporated. Purification by column
chromatography on silica gel using hexane/EtOAc = 20:1 as the eluent gave the corresponding
vinyl ether 1q (0.70 g, 39%). Vinyl ethers 1r–t were prepared by the same method (1r: 38%, 1s:
14%, 1t: 73%).
(S)-N-Boc Ser(OCH=CH2)OMe (1q): colorless oil; IR (neat, cmꢀ1) 3381, 3118, 2979, 2886,
1753, 1717; 1H NMR (500 MHz, CDCl3) δ 6.43 (dd, J = 14.0, 7.0 Hz, 1H), 5.37 (d (br), J = 7.5
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