DABO Boronate Promoted Conjugate Allylation of α,β-Unsaturated Aldehydes Using Copper(II) Catalysis

Article abstract of DOI:10.1021/acs.joc.6b00782

The first catalytic method for the selective 1,4-conjugate allylation of α,β-unsaturated aldehydes is reported. The method employs an air-stable diethanolamine-complexed boronic acid (DABO boronate) as the allyl transfer reagent and promotes conjugate add

Full text of DOI:10.1021/acs.joc.6b00782

Subscriber access provided by University of Sussex Library
Note
DABO Boronate Promoted Conjugate Allylation of alpha,beta-
Unsaturated Aldehydes using Copper(II) Catalysis
Pjotr Christiaan Roest, Nicholas Willet Mitchell Michel, and Robert A Batey
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00782 • Publication Date (Web): 30 Jun 2016
Downloaded from http://pubs.acs.org on July 4, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
α,β
DABO Boronate Promoted Conjugate Allylation of
-Unsaturated
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Aldehydes using Copper(II) Catalysis
Pjotr C. Roest, Nicholas W. M. Michel, Robert A. Batey*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St.
George Street, Toronto, ON, Canada, M5S 3H6
Corresponding Author E-mail: rbatey@chem.utoronto.ca
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 18
1
2
3
4
5
6
7
8
9
H
+
H
H
N
–
Cu(OAc)2 (cat)
O
B
R
O
R
O
O
15 examples
R = Alkyl, Aryl
Allyl DABO Boronate
yields up to 87%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1,4-selectivity up to 94:6
- AllylTransfer Reagent
- Iminium Activation
Abstract. The first catalytic method for the selective 1,4-conjugate allylation of α,β-unsaturated
aldehydes is reported. The method employs an air stable diethanolamine complexed boronic acid
(DABO boronate) as the allyl transfer reagent, and promotes conjugate addition over 1,2-
addition. A variety of aryl- and alkyl-substituted enals are tolerated, providing δ,ε-unsaturated
aldehyde products in good yields and selectivities under mild conditions.
ACS Paragon Plus Environment

Page 3 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Metal catalyzed conjugate addition to electron deficient olefins represents a versatile strategy for
preparing C–C bonds in a selective manner. Most approaches involve the use of copper or
rhodium catalysis, and a wide variety of electrophilic and nucleophilic partners have been
studied, contributing to its establishment as a fundamental transformation in organic
synthesis.1,2,3 Despite the ubiquity of such reactions, the conjugate allylation of α,β-unsaturated
aldehydes represents a particularly significant challenge with regard to controlling 1,2- over 1,4-
selectivity. Common strategies such as the use of organocopper reagents or the Hosomi-Sakurai
allylation are ineffective in the case of α,β-unsaturated aldehydes, owing to increased propensity
for 1,2-addition.4 In fact, the only examples of 1,4-selective allylation of enals were reported by
Maruoka and involve the use of allylithium or allylcerium reagents in the presence of a
fluorinated ATPH Lewis acid at cryogenic temperatures (-78 °C or -100 °C).5,6 Given the
versatility of the allyl group as a synthetic handle as well as the inherent reactivity of aldehydes,
we believed a convenient, catalytic protocol for such a transformation would be desirable. Herein
we report the development of a copper-catalyzed conjugate allylation of α,β-unsaturated
aldehydes using the crystalline and air-stable diethanolamine derived allyl DABO boronate.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Allylboron reagents have found widespread use both in direct and metal catalyzed allylation of
carbonyl groups, however these methods are typically selective for 1,2-addition.7 Yamamoto has
previously reported the copper catalyzed 1,4-allylation of electron deficient alkynes with
allylboronic acid pinacol ester, although the use of an alkynyl ketone led only to isolation of the
corresponding 1,2-addition product.8 It was envisioned that the use of iminium catalysis to
promote 1,4-addition could offer a potential solution.9 This general strategy has previously been
used for example by Cordova in the conjugate arylation of enals with aryl boronic acids using
Pd(OAc)2 in conjunction with Jørgensen’s catalyst.10 Disappointingly the combination of
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 18
1
2
3
4
5
6
7
8
9
catalytic Cu(OAc)2 and pyrrolidine with allyl boronic acid pinacol ester and cinnamaldehyde 1a
delivered the 1,2-addition adduct 2a as the major product, with only trace amounts of 3a
(Scheme 1a).11 Attempts to increase the selectivity with this system were unsuccessful, and in
particular it was found that increased amine concentrations led mostly to recovered starting
material and 2a as the sole product, indicating that pyrrolidine may be hampering the catalytic
cycle by coordinative saturation of the copper catalyst.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Initial approach to Cu(II) / amine promoted addition of allylboronic acid pinacol ester
to cinnamaldehyde and proposed pathway for iminium ion catalysis
a. Unsuccesful approach using allyl boronic acid pinacol ester
BPin
(1.5 equiv)
Cu(OAc)2 (10 mol%)
pyrrolidine (20 mol%)
H
OH
H
O
O
+
CH2Cl2, rt, 12 h
1a
2a : 3a
(> 95:5)
b. Proposed pathway for iminium formation using allyl DABO boronate 4.
H
O
H
+
+
R
N
NH
N
R
H
O
–
O
B
O
B
B
OH
O
O
O
4
4'
5
With this in mind, we turned to the diethanolamine complexed allyl boronic acid (DABO
boronate) 4, which was reported by Rychnovsky to be a competent allyl transfer reagent to
aldehydes and ketones in the presence of Brønsted acids.12 Since DABO boronates have been
shown to hydrolyze to boronic acids under aqueous conditions, it was hoped that the labile nature
of the B–N bond would allow this reagent to serve as a masked boronate and secondary amine
ACS Paragon Plus Environment

Page 5 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
for iminium ion activation of enals (Scheme 1b).13,14,15,16 This hypothesis was supported by
reports that aminoboranes can effectively generate iminium ions in Mannich-type reactions.17,18
Furthermore, the low inherent reactivity of allyl DABO boronate in the allylation of carbonyls
was anticipated to limit direct 1,2-addition. The addition of 4 to aldehyde 1a using Cu(OAc)2 (10
mol%) in dichloromethane led to an approximately 1:1 ratio of the 1,4- and 1,2 adducts 3a and
2a, respectively, albeit in modest yield (Table 1, Entry 1). Optimization of the reaction
conditions led to the identification of DMF as the best solvent, in combination with a 10 mol%
catalyst loading of Cu(OAc)2, with a 85:15 selectivity in favor of 1,4-addition and an isolated
yield of 80% of 3a (Entry 3). Although other copper sources were explored (e.g., Entries 4 and
5), they were found to be inferior to Cu(OAc)2. Selectivity could further be increased by slow
addition of 1a to a solution of 4 and Cu(OAc)2, delivering 3a with a 92:8 selectivity and in 87%
yield (Entry 6). A control experiment conducted in the absence of catalyst showed that copper is
required for 1,4-addition (Entry 8). Attempts at employing amine or phosphine based ligands
invariably led to a significant decrease in selectivity.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Optimization experiments for the conjugate allylation of cinnamaldehyde (1a)
H
H
OH
4 (1.5 equiv)
catalyst (10 mol %)
O
O
+
solvent, rt, 6 h
1a
3a
2a
Entry Solvent
Catalyst
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuCl2
Cu(acac)2
Cu(OAc)2
Cu(OAc)2
-
3a:2aa
52:48
72:28
86:14
68:32
70:30
92:8
Yield 3a (%)b
1
CH2Cl2
MeCN
DMF
DMF
DMF
DMF
DMF
DMF
29
57
78
59
63
87
73
2
3
4
5
6c
7c, d
8
89:11
<5:95
e
-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 18
1
2
3
4
5
6
7
8
a
1
Ratios determined by H NMR analysis of the crude reaction mixture using the alkenyl proton
signals. b Isolated yields after column chromatography. c Reaction conducted by slow addition of
1a over 20 h followed by stirring for an additional 4 h. d Reaction conducted using 1.1 equiv of 4.
e Incomplete conversion (30%) of starting material was observed. Yield Not Determined.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Given the prolonged reaction time and the use of an excess of 4, the possibility of double
allylation was a concern. Over the course of optimizing the reaction conditions, it was found that
the workup procedure employed was crucial in avoiding this undesired pathway. While
quenching immediately with saturated aq. NH4Cl led to the formation of a mixture of mono- and
bis-allylated products in a 4:1 ratio, quenching the reaction with 10 equivalents of acetic acid to
destroy excess 4, followed by neutralization with saturated aq. NaHCO3 provided the desired
product without the formation of the double allylation product. This indicates that aldehyde 3a is
only formed after aqueous workup at which point it can react with remaining 4. A possible
explanation is the initial formation of a stable boron enolate intermediate, as previously reported
by Morken in the nickel catalyzed conjugate allylation of activated enones.19
Having determined the optimal conditions, the substrate scope was evaluated using a variety of
aryl-substituted enals (Table 2). A variety of both electron rich (Entries 2, 3, 8-10) and electron
poor aromatics (Entry 4), as well as halogenated substrates (Entries 5-7) are amenable to
addition. Substituents at the ortho or meta positions of 1 were also well tolerated (Entries 8 and
9) and furan 1j was also found to be a suitable substrate (Entry 10). In general, it was found that
electron rich substrates reacted with slightly higher selectivity than electron poor aromatics. The
use of substituted allyl boronates, such as (E)-crotyl DABO boronate was unsuccessful and
furnished only the 1,2-addition products.
ACS Paragon Plus Environment

Page 7 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Conjugate allylation of aryl substituted enals 3a-j
4 (1.5 equiv)
Cu(OAc)2 (10 mol %)
H
H
OH
+
R
O
R
O
R
DMF, rt, 24 h
slow addition
1a-j
3a-j
2a-j
Entry
1
Substrate
Product
Yield (%)a Ratio (3:2)b
1a
3a
87
83
87
92:8
90:10
94:6
2
3
1b
1c
3b
3c
4
1d
3d
76
86:14
5
6
7
8
9
1e
1f
3e
3f
80
81
84
88
80
90:10
90:10
90:10
94:6
1g
1h
1i
3g
3h
3i
90:10
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 18
1
2
3
4
10
1j
3j
75
88:12
5
6
7
8
9
a
b
1
Isolated yields after column chromatography. Ratios determined by H NMR analysis of the
crude reaction mixture using the alkenyl proton signals.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The reaction of alkyl-substituted enals using the previously established protocol furnished
numerous by-products other than those arising from 1,2- or 1,4-allylation. This is presumably
due to the increased reactivity of unconjugated enals that could favor polymerization pathways
and reactions via iminium ion and enamine intermediates. Cooling the reaction to 0 °C and
adding 5 equivalents of methanol was sufficient to eliminate these issues.20 Although slow
addition of the aldehyde was incompatible with the presence of methanol, good selectivities
could still be obtained by increasing the Cu(OAc)2 catalyst loading to 25 mol % (Table 3). Under
these conditions, both primary (Entry 1) and secondary alkyl substituents (Entry 2) were
tolerated, as well as a variety of protected alcohols (Entries 3-5). Interestingly, submitting
acrolein to these reaction conditions afforded only the corresponding 1,2-addition product.
Table 3. Conjugate allylation of alkyl substituted enals 3k-o
4 (1.5 equiv)
Cu(OAc)2 (25 mol %)
H
H
OH
+
R
O
R
O
R
MeOH (5 equiv)
DMF, 0 °C, 6 h
1k-o
3k-o
2k-o
Entry
1
Enal
Product
Yield (%)a Ratio (3:2)b
1k
1l
3k
81
86:14
2
3l
75
80:20
ACS Paragon Plus Environment

Page 9 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
3
4
5
1m
1n
1o
3m
3n
3o
74
77
76
84:16
82:18
80:20
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
b
1
Isolated yields after column chromatography. Ratios determined by H NMR analysis of the
crude reaction mixture using the alkenyl proton signals.
To demonstrate the synthetic utility of the resulting products aldehyde 3n was prepared on a 5
mmol scale and subjected to a one pot Wacker-Tsuji oxidation/condensation sequence to afford
5-substituted cyclohexenone 6 in 60% yield (Scheme 2).21 Compound 6 was recently used as an
intermediate in the total synthesis of huperzine Q.22
Scheme 2. Preparation of cyclohexenone 6
In summary, allyl DABO boronate was shown to be an effective reagent for the conjugate
allylation of α,β-unsaturated aldehydes using copper catalysis. In contrast with previous
methods, which require the use of air sensitive reagents and cryogenic temperatures, this
approach utilizes air stable reagents at or near room temperature and tolerates a wide variety of
functional groups. The resulting products contain aldehyde and alkene functional groups that can
be elaborated to afford synthetically useful intermediates. Finally, this study represents the first
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 18
1
2
3
4
5
6
example of the use of DABO boronates to promote 1,4-addition, expanding upon the known
reactivity of these compounds.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental Section
All reactions were performed under argon in flame-dried glassware unless otherwise indicated.
Anhydrous dimethylformamide was obtained as ≥ 99.9 % pure and stored under argon. Flash
chromatography on silica gel (60 Å, 230-400 mesh) was performed with reagent grade solvents.
Analytical thin-layer chromatography (TLC) was performed on pre-coated silica gel plates and
visualized with a UV254 lamp. Solvent ratios for chromatography and Rf values are reported as
v/v ratios. All 1-D (1H, 13C) NMR spectra were obtained on a 400 MHz spectrometer as solutions
in deuterated solvents. Chemical shifts are reported in δ ppm values. Proton chemical shifts were
internally referenced to the residual proton resonance in CDCl3 (δ 7.26 ppm). Carbon chemical
shifts were internally referenced to the solvent resonance in CDCl3 (δ 77.16 ppm). Peak
multiplicities are designated by the following abbreviations: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br, broad; J, coupling constant in Hz (rounded to the nearest 0.5 Hz). Exact
mass measurements were performed on quadrupole time-of-flight mass spectrometers utilizing
direct analysis in real time ionization (DART-TOF).
Allyl DABO Boronate (4).12 Prepared according to a known literature procedure and purified by
recrystallization from MeCN. Excess diethanolamine in crude 4 is detrimental to the catalyst
activity and thus recrystallization is required to obtain good selectivities.
ACS Paragon Plus Environment

Page 11 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Conjugate Allylation of Aryl Substituted Enals (Method A). To a round bottom flask
equipped with a magnetic stirrer charged with allyl DABO boronate 4 (116.3 mg, 0.75 mmol, 1.5
equiv) and Cu(OAc)2 (9.1 mg, 0.050 mmol, 0.10 equiv) was added DMF (3 mL). In a vial, enal 1
(0.50 mmol, 1.0 equiv) was dissolved in DMF (2 mL). This solution was added to the round
bottom flask over 20 h using a syringe pump. Stirring was maintained for an additional 4 h after
the addition was complete. The reaction was quenched with AcOH (0.29 mL, 5.0 mmol, 10
equiv) and stirred for 30 min before neutralizing with saturated aq. NaHCO3 (15 mL). The
resulting solution was extracted with Et2O (3 x 15 mL) and the combined organics were washed
with brine (15 mL) and dried over anhydrous Na2SO4. The solvent was removed in vacuo and
the crude mixture was purified by flash column chromatography over silica gel.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-Phenylhex-5-enal (3a).23 Eluted using 5:95 EtOAc:hexanes. Colorless oil (75.8 mg, 87%). Rf
0.43 (10:90 EtOAc:hexanes). Spectral data were identical to those previously reported.
3-(p-Tolyl)hex-5-enal (3b). Eluted using 3:97 EtOAc:hexanes. Colorless oil (78.3 mg, 83%). Rf
0.56 (10:90 EtOAc:hexanes); IR (thin film in CH2Cl2) νmax 3053, 2986, 2924, 1721, 1709, 1516,
1
1441, 1422 cm-1; H NMR (400 MHz, CDCl3) δ 9.67 (1H, t, J = 2.0 Hz), 7.15–7.06 (4H, m),
5.67 (1H, dddd, J = 17.0, 10.0, 7.5, 6.5 Hz), 5.07–4.96 (2H, m), 3.32–3.22 (1H, m), 2.81–2.64
13
(2H, m), 2.49–2.34 (2H, m), 2.32 (3H, s); C NMR (100 MHz, CDCl3) δ 202.0, 140.4, 136.3,
136.0, 129.4, 127.4, 117.2, 49.6, 41.1, 39.5, 21.1; HRMS (DART) mass calcd for C13H16O [M +
H]+: 189.1279, found 189.1286.
3-(4-Methoxyphenyl)hex-5-enal (3c). Eluted using 7:93 EtOAc:hexanes. Colorless oil (88.5
mg, 87%). Rf 0.30 (10:90 EtOAc:hexanes); IR (thin film in CH2Cl2) νmax 3053, 2988, 1713, 1514,
1421 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.66 (1H, t, J = 2.0 Hz), 7.15–7.08 (2H, m), 6.88–6.82
(2H, m), 5.66 (1H, dddd, J = 17.0, 10.0, 7.5, 6.5 Hz), 5.05–4.96 (2H, m), 3.78 (4H, s), 3.30–3.20
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 18
1
2
3
4
13
(1H, m), 2.80–2.61 (2H, m), 2.45–2.30 (2H, m); C NMR (100 MHz, CDCl3) δ 202.0, 158.4,
5
6
7
8
9
136.0, 135.5, 128.5, 117.2, 114.1, 55.3, 49.7, 41.3, 39.1; HRMS (DART) mass calcd for
C13H16O2 [M + H]+: 205.1229, found 205.1226.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-(4-Nitrophenyl)hex-5-enal (3d). Eluted using 20:80 EtOAc:hexanes. Yellow oil (83.1 mg,
76%). Rf 0.15 (10:90 EtOAc:hexanes); IR (thin film in CH2Cl2) νmax 3057, 2928, 1724, 1607,
1
1597, 1522, 1506, 1348, 1265 cm-1; H NMR (400 MHz, CDCl3) δ 9.70 (1H, t, J = 1.5 Hz),
8.26–8.05 (2H, m), 7.44–7.31 (2H, m), 5.60 (1H, ddt, J = 16.5, 10.5, 7.0 Hz), 5.09–4.90 (2H, m),
3.45 (1H, p, J = 7.5 Hz), 2.94–2.74 (2H, m), 2.41 (2H, tq, J = 7.0, 1.2 Hz); 13C NMR (100 MHz,
CDCl3) δ 200.2, 151.4, 146.9, 134.8, 128.6, 124.0, 118.2, 49.1, 40.5, 39.3; HRMS (DART) mass
calcd for C12H13NO3 [M + H]+: 220.0974, found 220.0972.
3-(4-Fluorophenyl)hex-5-enal (3e). Eluted using 5:95 EtOAc:hexanes. Colorless oil (77.1 mg,
80%). Rf 0.43 (10:90 EtOAc:hexanes); IR (thin film in CH2Cl2) νmax 3055, 2986, 1724, 1640,
1605, 1510, 1422, 1225, 1159 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.67 (1H, t, J = 2.0 Hz, 1H),
7.20–7.10 (2H, m), 7.04–6.95 (2H, m), 5.70–5.57 (1H, m), 5.06–4.96 (2H, m), 3.36–3.24 (1H,
m), 2.84–2.63 (2H, m), 2.37 (2H, t, J = 7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 201.4, 161.7 (d,
J = 245.0 Hz), 139.2 (d, J = 3.0 Hz), 129.0 (d, J = 7.5 Hz), 117.5, 115.6 (d, J = 21.0 Hz), 49.6,
41.1, 39.1; HRMS (DART) mass calcd for C12H13FO [M + H]+: 193.1029, found 193.1036.
3-(4-Chlorophenyl)hex-5-enal (3f). Eluted using 6:94 EtOAc:hexanes. Colorless oil (84.3 mg,
81%). Rf 0.39 (10:90 EtOAc:hexanes); IR (thin film in CH2Cl2) νmax 3053, 2988, 1709, 1493,
1422 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.66 (1H, t, J = 2.0 Hz), 7.30–7.24 (2H, m), 7.16–7.10
(2H, m), 5.69–5.55 (1H, m), 5.05–4.95 (2H, m), 3.34–3.23 (1H, m), 2.83–2.64 (2H, m), 2.37
(2H, tt, J = 7.0, 1.5 Hz); 13C NMR (100 MHz, CDCl3) δ 201.2, 142.0, 135.4, 132.5, 129.0, 128.9,
ACS Paragon Plus Environment

Page 13 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
117.6, 49.4, 40.9, 39.1; HRMS (DART) mass calcd for C12H13ClO [M + H]+: 209.0733, found
209.0729.
7
8
9
3-(4-Bromophenyl)hex-5-enal (3g). Eluted using 6:94 EtOAc:hexanes. Colorless oil (106.5 mg,
84%). Rf 0.39 (10:90 EtOAc:hexanes); IR (thin film in CH2Cl2) νmax 3053, 2986, 1713, 1491,
1422 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.67 (1H, t, J = 2.0 Hz), 7.47–7.37 (2H, m), 7.11–7.04
(2H, m), 5.69–5.55 (1H, m), 5.06–4.95 (2H, m), 3.33–3.21 (1H, m), 2.83–2.62 (2H, m), 2.37
(2H, tt, J = 7.0, 1.5 Hz); 13C NMR (100 MHz, CDCl3) δ 201.1, 142.6, 135.4, 131.8, 129.4, 120.5,
117.7, 49.4, 40.8, 39.2; HRMS (DART) mass calcd for C12H13BrO [M + H]+: 253.0228, found
253.0223.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-(2-Methoxyphenyl)hex-5-enal (3h). Eluted using 5:95 EtOAc:hexanes. Colorless oil (89.7
mg, 88%). Rf 0.38 (10:90 EtOAc:hexanes); IR (thin film in CH2Cl2) νmax 3053, 2986, 2839,1709,
1
1601, 1586, 1493, 1464, 1439, 1030 cm-1; H NMR (400 MHz, CDCl3) δ 9.65 (1H, t, J = 2.5
Hz), 7.20 (1H, ddd, J = 8.0, 7.5, 2.0 Hz), 7.14 (1H, dd, J = 7.5, 2.0 Hz), 6.92 (1H, td, J = 7.5, 1.0
Hz), 6.87 (1H, dd, J = 8.0, 1.0 Hz), 5.70 (1H, dddd, J = 17.0, 10.0, 7.5, 6.5 Hz), 5.07–4.94 (2H,
m), 3.83 (3H, s), 3.77–3.66 (1H, m), 2.80–2.63 (2H, m), 2.54–2.44 (1H, m), 2.39 (1H, dtt, J =
14.0, 7.5, 1.0 Hz); 13C NMR (100 MHz, CDCl3) δ 202.7, 157.1, 136.4, 131.3, 128.0, 127.7,
120.8, 116.9, 110.8, 55.4, 48.4, 39.2, 33.4; HRMS (DART) mass calcd for C13H16O2 [M + H]+:
205.1229, found 205.1231.
3-(3,5-Dimethoxyphenyl)hex-5-enal (3i). Eluted using 10:90 EtOAc:hexanes. Colorless oil
(93.9 mg, 80%). Rf 0.28 (10:90 EtOAc:hexanes); IR (thin film in CH2Cl2) νmax 3055, 1724, 1607,
1597, 1464, 1431, 1206, 1153 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.67 (1H, t, J = 2.0 Hz), 6.35
(2H, d, J = 2.0 Hz), 6.32 (1H, t, J = 2.0 Hz), 5.67 (1H, dddd, J = 16.5, 10.0, 8.0, 6.5 Hz), 5.08–
4.97 (2H, m), 3.78 (6H, s), 3.22 (1H, p, J = 7.5 Hz), 2.79–2.61 (2H, m), 2.38 (2H, tddd, J = 14.0,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 18
1
2
3
4
5
6
7
8
9
13.0, 8.0, 7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 201.8, 161.1, 146.0, 135.8, 117.3, 105.8, 98.4,
55.4, 49.3, 40.9, 40.2; HRMS (DART) mass calcd for C14H18O3 [M + H]+: 235.1334, found
235.1337.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-(Furan-2-yl)hex-5-enal (3j).23 Eluted using 8:92 EtOAc:hexanes. Yellow oil (61.4 mg, 75%).
Rf 0.28 (10:90 EtOAc:hexanes). Spectral data were identical to those previously reported.
Conjugate Allylation of Alkyl Substituted Enals (Method B). To a round bottom flask
equipped with a magnetic stirrer charged with allyl DABO boronate 4 (116.3 mg, 0.75 mmol, 1.5
equiv) and Cu(OAc)2 (22.7 mg, 0.125 mmol, 0.25 equiv) was added DMF (3 mL). The resulting
solution was cooled to 0 °C before adding MeOH (0.10 mL, 2.5 mmol, 5 equiv) followed by enal
1. The reaction was stirred for 6 h. The workup procedure was identical to method A.
3-Phenethylhex-5-enal (3k). Eluted using 5:95 EtOAc:hexanes. Colorless oil (82.1 mg, 81%).
Rf 0.38 (10:90 EtOAc:hexanes); IR (thin film in CH2Cl2) νmax 3050, 2988, 1684, 1640, 1422 cm-
1; 1H NMR (400 MHz, CDCl3) δ 9.75 (1H, t, J = 2.0 Hz), 7.33–7.24 (2H, m), 7.23–7.13 (3H, m),
5.74 (1H, ddt, J = 16.0, 11.0, 7.0 Hz), 5.13–5.01 (2H, m), 2.63 (2H, ddd, J = 9.0, 7.0, 2.5 Hz),
2.50–2.33 (2H, m), 2.29–2.18 (1H, m), 2.12 (2H, dddd, J = 14.0, 13.0, 9.5, 6.5 Hz), 1.76–1.58
13
(2H, m); C NMR (100 MHz, CDCl3) δ 202.7, 142.1, 135.9, 128.6, 128.4, 126.0, 117.5, 48.1,
38.4, 35.9, 33.2, 32.5; HRMS (DART) mass calcd for C14H18O [M + H]+: 203.1436, found
203.1442.
3-Cyclohexylhex-5-enal (3l). Eluted using 2:98 EtOAc:hexanes. Colorless oil (67.4 mg, 75%).
Rf 0.60 (10:90 EtOAc:hexanes); IR (thin film in CH2Cl2) νmax 2987, 2928, 2855, 1709, 1449,
1
1421 cm-1; H NMR (400 MHz, CDCl3) δ 9.73 (1H, t, J = 2.0 Hz), 5.71 (1H, dddd, J = 16.0,
11.5, 7.5, 6.5 Hz), 5.05–4.97 (2H, m), 2.34 (2H, qdd, J = 17.0, 6.0, 2.0 Hz), 2.24–2.13 (1H, m),
2.01–1.90 (2H, m), 1.78–1.69 (2H, m), 1.69–1.56 (3H, m), 1.39–1.28 (1H, m), 1.27–1.06 (3H,
ACS Paragon Plus Environment

Page 15 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
13
m), 1.05–0.90 (2H, m); C NMR (100 MHz, CDCl3) δ 203.4, 137.2, 116.9, 45.7, 40.8, 38.2,
36.3, 30.3, 29.7, 26.8, 26.7; HRMS (DART) mass calcd for C12H20O [M + H]+: 181.1592, found
181.1589.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(2-Oxoethyl)pent-4-en-1-yl acetate (3m). Eluted using 16:84 EtOAc:hexanes. Colorless oil
(63.2 mg, 74%). Rf 0.14 (10:90 EtOAc:hexanes); IR (thin film in CH2Cl2) νmax 3055, 2988, 1724,
1640, 1421 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.77 (1H, t, J = 1.5 Hz), 5.73 (1H, ddt, J = 16.5,
10.5, 7.0 Hz, 1H), 5.12–5.03 (2H, m), 4.15–4.06 (1H, m), 3.99–3.90 (1H, m), 2.54–2.38 (3H, m),
2.24–2.15 (1H, m), 2.14–2.07 (1H, m), 2.04 (3H, s); 13C NMR (100 MHz, CDCl3) δ 201.0,
170.7, 134.7, 117.8, 66.3, 45.4, 35.5, 32.2, 20.7; HRMS (DART) mass calcd for C9H14O3 [M +
H]+: 171.1021, found 171.1022.
3-((Benzyloxy)methyl)hex-5-enal (3n).24 Eluted using 5:95 EtOAc:hexanes. Colorless oil (84.0
mg, 77%). Rf 0.36 (10:90 EtOAc:hexanes). Spectral data were identical to those previously
reported.
3-(((tert-Butyldimethylsilyl)oxy)methyl)hex-5-enal (3o). Eluted using 3:97 EtOAc:hexanes.
Colorless oil (92.3 mg, 76%). Rf 0.57 (10:90 EtOAc:hexanes); IR (thin film in CH2Cl2) νmax
2957, 2930, 2857, 1705, 1464, 1421, 1101 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.76 (1H, dd, J =
2.5, 2.0 Hz), 5.81–5.66 (1H, m), 5.08–4.99 (2H, m), 3.60 (1H, dd, J = 10.0, 4.5 Hz, 1H), 3.45
(1H, dd, J = 10.0, 6.5 Hz), 2.49–2.31 (2H, m), 2.29–2.12 (2H, m), 2.02 (1H, dtt, J = 14.0, 7.0,
13
1.0 Hz), 0.87 (9H, s), 0.02 (6H, s); C NMR (100 MHz, CDCl3) δ 202.7, 136.1, 117.2, 65.6,
46.0, 36.3, 35.7, 26.0, 18.4, -5.4; HRMS (DART) mass calcd for C13H26O2Si [M + H]+:
243.1780, found 243.1776.
Synthesis of enone 6. To a round bottom flask equipped with a magnetic stirrer charged with
CuCl (148.5 mg, 1.5 mmol, 1.5 equiv) and PdCl2 (35.5 mg, 0.20 mmol, 0.2 equiv) was added
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 18
1
2
3
4
5
6
7
8
9
DMF (5 mL) and water (1 mL). To this solution was added aldehyde 3n (218.3 mg, 1 mmol, 1
equiv) and the reaction vessel was purged with O2 (balloon). The reaction was stirred for 24 h
under O2 atmosphere before addition of NaOMe (1.08 g, 20 mmol, 20 equiv), after which stirring
was maintained for an additional 12 h. The solution was diluted with saturated aq. NH4Cl (10
mL) and extracted with Et2O (3 x 15 mL). The combined organics were dried over anhydrous
Na2SO4. The solvent was removed in vacuo and the crude mixture was purified by flash column
chromatography over silica gel.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5-((Benzyloxy)methyl)cyclohex-2-en-1-one (6).25 Eluted using 25:75 EtOAc:hexanes. Colorless
oil (129.6 mg, 60%). Rf 0.34 (25:75 EtOAc:hexanes). Spectral data were identical to those
previously reported.
Acknowledgements. The authors thank the University of Toronto and the Natural Science and
Engineering Research Council of Canada (NSERC) for financial support. P.C.R. is grateful to
the University of Toronto for an Edwin Walter Warren Scholarship and to the Ontario Ministry
of Education for an Ontario Graduate Scholarship. N.W.M.M. is grateful to NSERC for a
NSERC USRA. P.C.R. thanks Kyan D'Angelo for helpful discussions.
Supporting Information. Spectral data for all compounds including 1H and 13C NMR.
REFERENCES
1 For a general review, see: Christoffers, J.; Koripelly, G.; Rosiak, A.; Rössle M. Synthesis 2007,
9, 1279–1300.
ACS Paragon Plus Environment

Page 17 of 18
The Journal of Organic Chemistry
1
2
3
4
5
2
For a review on rhodium catalyzed methods, see: Edwards, H. J.; Hargrave, J. D.; Penrose, S.
6
7
8
9
D.; Frost, C.G. Chem. Soc. Rev. 2010, 39, 2093–2105.
3
For a review on copper catalyzed methods, see: Alexakis, A.; Bäckvall, J. E.; Krause, N.;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Pàmies, O.; Diéguez, M. Chem. Rev. 2008, 108, 2796–2823.
4 Majetich, G.; Casares, A.; Chapman, D.; Behnke, M. J. Org. Chem. 1986, 51, 1745-1753.
5 Ooi, T.; Kondo, Y.; Maruoka, K. Angew. Chem. Int. Ed. 1997, 36, 1183–1185.
6 Ooi, T.; Miura, T.; Kondo, Y.; Maruoka, K. Tetrahedron Lett. 1997, 38, 3947–3950.
7 Kennedy, J. W. J.; Hall, D.G. Angew. Chem. Int. Ed. 2003, 42, 4732–4739.
8 Yamamoto, Y.; Yamada, S.; Nishiyama, H. Chem. Eur. J. 2012, 18, 3153–3156.
9
For a review on iminium catalysis, see: Erkkilä, A.; Majander, I.; Pihko, P. M. Chem. Rev.
2007, 107, 5416–5470.
10 Ibrahem, I.; Ma, G.; Afewerki, S.; Córdova, A. Angew. Chem. Int. Ed. 2013, 52, 878–882.
11 In the absence of pyrrolidine, 1,4-addition product was not observed.
12 Reilly, M. K.; Rychnovsky, S. D. Org. Lett. 2010, 12, 4892–4895.
13 Schinazi, R. F.; Prusoff, W. H. J. Org. Chem. 1985, 50, 841–847.
14 For a review on DABO boronates, see: Bonin, H.; Delacroix, T.; Gras, E. Org. Biomol. Chem.
2011, 9, 4714–4724.
15
Preliminary experiments support this pathway. Replacing 4 with the corresponding N-
methyldiethanolamine analogue did not afford any 1,4-addition product, presumably because it is
unable to form the iminium intermediate. However, NMR experiments conducted in the presence
of methyl DABO boronate and cinnamaldehyde indicate the formation of a hemiaminal,
demonstrating the ability of DABO boronates to act as masked secondary amines (see
Supporting Information).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 18
1
2
3
4
5
6
7
16 Bonin, H.; Leuma-Yona, R.; Marchiori, B.; Demonchaux, P.; Gras, E. Tetrahedron Lett. 2011,
52, 1132-1135.
8
17 Suginome, M.; Uehlin, L.; Yamamoto, A.; Murakami, M. Org. Lett. 2004, 6, 1167–1169.
18 Suginome, M.; Uehlin, L.; Murakami, M. J. Am. Chem. Soc. 2004, 126, 13196–13197.
19 Sieber, J. D.; Morken, J. P. J. Am. Chem. Soc. 2008, 130, 4978–4983.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
20
The presence of excess methanol may serve to quench potential reactive intermediates before
they can undergo undesired side reactions.
21
A similar sequence was previously used in the total synthesis of platencin: Nicolaou, K. C.;
Scott Tria, G.; Edmonds, D. J.; Kar, M. J. Am. Chem. Soc. 2009, 131, 15909–15917.
22 Hong, B.; Li, H.; Wu, J.; Zhang, J.; Lei, X. Angew. Chem. Int. Ed. 2015, 54, 1011–1015.
23 Allin, S. M.; Horro-Pita, C.; Essat, M.; Aspinall, I.; Shah, P. Synth. Commun. 2010, 40, 2696–
2711.
24 LaMarche, M. J.; Leeds, J.A.; Amaral, A.; Brewer, J. T.; Bushell, S. M.; Deng, G.; Dewhurst,
J. M.; Ding, J.; Dzink-Fox, J.; Gamber, G.; Jain, A.; Lee, K.; Lee, L.; Lister, T.; McKenney, D.;
Mullin, S.; Osborne, C.; Palestrant, D.; Patane, M. A.; Rann, E. M.; Sachdeva, M.; Shao, J.;
Tiamfook, S.; Trzasko, A.; Whitehead, L.; Yifru, A.; Yu, D.; Yan, W.; Zhu, Q. J. Med.Chem.
2012, 55, 2376–2387.
25 Taber, D. F.; Kanai, K.; Jiang, Q.; Bui, G. J. Am. Chem. Soc. 2000, 122, 6807–6808.
ACS Paragon Plus Environment