Iron-Catalyzed Synthesis of C2 Aryl- and N-Heteroaryl-Substituted Tetrahydropyrans

Article abstract of DOI:10.1021/acs.joc.5b02371

An iron-catalyzed cyclization of hydroxy allylic derivatives into tetrahydropyrans possessing an N-heteroaryl at C2 is disclosed. The reaction proceeds with good yield and in high diastereoselectivity in favor of the more stable isomer. The diastereoselectivity results from an iron-induced reopening of the tetrahydropyrans, allowing a thermodynamic equilibration. The method allows access to a variety of 2,6-disubstituted as well as 2,4,6-trisubstituted tetrahydropyrans that could be considered as attractive scaffolds for the pharmaceutical industry.

Full text of DOI:10.1021/acs.joc.5b02371

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Article
Iron-Catalyzed Synthesis of C2 Aryl and N-
Heteroaryl Substituted Tetrahydropyrans
Cyril Bosset, Patrick Angibaud, Ian Stanfield, Lieven Meerpoel,
Didier Berthelot, Amandine Guérinot, and Janine Cossy
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02371 • Publication Date (Web): 11 Nov 2015
Downloaded from http://pubs.acs.org on November 12, 2015
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Iron-Catalyzed Synthesis of C2 Aryl and N-Heteroaryl Substituted Tetrahydropyrans
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Cyril Bosset,a Patrick Angibaud,b Ian Stanfield,b Lieven Meerpoel,c Didier Berthelot,b
Amandine Guérinot*a and Janine Cossy*a
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aLaboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI)-
UMR 8231, ESPCI ParisTech, CNRS, 10 rue Vauquelin 75231 Paris Cedex 05, France.
bJanssen Research & Development, Oncology Medicinal Chemistry, Campus de Maigremont-
BP615-27106, Val de Reuil Cedex, France.
cJanssen Research & Development, Janssen Pharmaceutica N.V. Turnhoutsweg 30, 2340
Beerse, Belgium.
janine.cossy@espci.fr; amandine.guerinot@espci.fr
tel: 33 140794429
R1O
OH
Ph
Ph
FeCl3l6H O
2
(N-Het)Ar
O
(N-Het)Ar
R2
R2
R1 = H, Ac
R2 = H, OH, Ph
15 examples
11-94%
dr up to 99:1
Abstract
An iron-catalyzed cyclization of hydroxy allylic derivatives into tetrahydropyrans possessing
a N-heteroaryl at C2 is disclosed. The reaction proceeds with good yield and in high
diastereoselectivity in favor of the more stable isomer. The diastereoselectivity results from
an iron-induced re-opening of the tetrahydropyrans allowing a thermodynamic equilibration.
The method allows the access to a variety of 2,6-disubstituted as well as 2,4,6-trisubstituted
tetrahydropyrans that could be considered as attractive scaffolds for the pharmaceutical
industry.
Introduction
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Substituted tetrahydropyrans (THPs) are ubiquitous motifs in natural and non-natural
biologically active products and some examples are depicted in Figure 1.1 Among them,
2-aryl/heteroaryl THPs exhibit a wide range of biological properties including cytotoxicity,
tumor growth inhibition, inhibition of tyrosine kinase and dipeptidyl peptidase 4 which is
involved in type 2 diabetes.2
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Figure 1. Tetrahydropyran units in biologically active natural products
HO
OMe
O
O
O
O
HO
(-)-Centrolobine
Aspergillide A
OEt
OMe
O
O
H
H
Cl
O
O
OMe
NH
OH
O
O
O
HO
OH
OH
O
N
Dapaglifozin
(+)-Neopeltolide
Due to their potent pharmacological properties, a myriad of synthetic methods has been
developed for the construction of THP rings.3 Among the existing methods, the metal-
catalyzed cyclization of hydroxy allylic alcohols of type A emerged as an efficient and
stereoselective strategy to access THPs of type B. In addition, as water is the only by-product,
this reaction meets the current environmental requirements that encourage the development of
eco-friendly and atom-economic processes (Scheme 1).
Scheme 1. Metal-catalyzed cyclization of mono-allylic diols
HO
R1 OH
R2
R1
O
R2
[M] cat.
H2O
B
A
For a long time, Pd(II)-catalysis ruled out the field of metal-catalyzed heterocyclizations and a
large array of substituted THPs has been formed through intramolecular oxypalladation. A
1,3-chirality transfer was responsible for the high diastereoselectivity of the reaction (Scheme
2).4
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Scheme 2. Pd(II)-catalyzed synthesis of tetrahydropyrans
5
OH
6
7
PdCl2(CH3CN)2
(10 mol %)
H
H
O
OH
8
9
0 °C, THF
72%
(S,R)-1a
cis-2a
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OH
H
H
PdCl2(CH3CN)2
(10 mol %)
OH
O
0 °C, THF
79%
(S,S)-1a
trans-2a
A few years later, Au(I)-catalyzed cyclizations of hydroxy allylic alcohols, processing
through a SN2’ pathway, were developed delivering THPs in good yields and
stereoselectivities. A 1,3-chirality transfer is the key to account for the high stereoselectivity
and enantiomers can be obtained by switching the geometry of the double bond (Scheme 3).5
Scheme 3. Au-catalyzed synthesis of tetrahydropyrans
Ph
HO
(R)
PPh3AuCl/AgOTf
(1 mol %)
H
OH
O
Ph
Ph
MS 4 Å, rt, CH2Cl2
(E)-1b
(S)-2b
Ph
H
O
PPh3AuCl/AgOTf
(1 mol %)
(R)
OH
OH
MS 4 Å, rt, CH2Cl2
(R)-2b
(Z)-1b
Despite their recognized utility, palladium and gold catalysis have to face some drawbacks
such as high costs, limited supply and toxicity.6,7 Furthermore, only few examples of metal-
catalyzed heterocyclizations of hydroxy allylic and/or benzylic alcohols delivering 2-aryl
THPs have been reported so far8,9 and, to the best of our knowledge, the preparation of 2-N-
heteroaryl THPs using this cyclization strategy has not yet been described, maybe due to the
Lewis basicity of N-heteroaromatics that could poison the metal catalyst.10
During the past decade, a growing interest has been devoted to iron catalysis.11 Besides being
cheap and low-toxic, iron salts exhibit attractive chemical properties including the ability to
activate allylic and/or benzylic alcohols.12 In 2010, we reported the highly diastereoselective
FeCl3-catalyzed formation of 2,6-disubstituted THPs.13 This method was extended to the
synthesis of a wide variety of THP units including 2,4,6-trisubstituted THPs but was restricted
so far to alkyl, ester, alkenyl or hydroxyl C2 and C4 substituents (Scheme 4).14,15
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Scheme 4. Iron-catalyzed synthesis of 2,6- and 2,4,6-substituted THPs
R3
5
6
7
8
HO
R1 OH
R3
R1
2
O
FeCl3l6H O (5 mol %)
2
2
6
6
4
4
rt, CH2Cl2
9
51-99%
R2
R2
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A
B
R1 = Alk, CO2Et
R2 = H, OH
R3 = Ar, Me
(dr up to 98:2)
11 examples
In this study, we focused on the preparation of 2-aryl and 2-N-heteroaryl THPs and a full
account of our results is reported herein.
Results and discussion
Synthesis of C2 aryl-tetrahydropyrans
Based on our previous results obtained for the formation of 2,6-disubstituted THPs possessing
an alkyl substituent at C2, we decided to treat the hydroxyl-acetate 3 with a catalytic amount
of FeCl3Ÿ6H2O (5 mol %).16 The presence of a benzylic alcohol and a benzylic acetate in the
starting material was first envisioned as a potent difficulty but, pleasingly, the cyclization of
hydroxy acetate 3 proceeded smoothly furnishing THP 4 as a single cis-diastereomer in good
yield (90%) (Scheme 5).
Scheme 5. Synthesis of a C2-Ar tetrahydropyran
AcO
OH
Ph
Ph
Ph
Ph
O
FeCl3l6H O (5 mol %)
2
rt, 2 h, CH2Cl2
3
4
90%
(dr > 98:2)
The method also allowed the access to 2,4,6-trisubstituted THPs. To introduce a phenyl group
at the C4 position, a Sakurai allylation was performed on (E)-chalcone and the corresponding
ketone was reduced to give a mixture of diastereomeric alcohols syn-5 and anti-5, which were
separated by flash chromatography on silica gel. A cross-metathesis of syn-5 and anti-5 with
1-phenylallyl acetate in the presence of the second generation Grubbs-Hoveyda catalyst G-
HII catalyst furnished respectively allylic acetates syn-6 and anti-6 in 41% yield in both cases
(Scheme 6).
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Scheme 6. Preparation of allylic acetates syn-6 and anti-6
5
6
7
8
SiMe3
1/
O
OH Ph
OH Ph
I2 (20 mol %)
2/ NaBH4
Ph
Ph
Ph
Ph
syn-5
(38%)
anti-5
(25%)
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MesN NMes
G-HII (10 mol %)
50 °C, 24 h, CH2Cl2
41%
41%
Cl
Cl
O
Ru
OH Ph
OAc
Ph
OH Ph
OAc
Ph
G-H II
Ph
Ph
syn-6
anti-6
When anti-6 was treated with FeCl3Ÿ6H2O (5 mol %), the corresponding cis-2,4,6-
trisubstituted THP 7a was isolated as a single diastereomer with a good yield of 82% after
only 1 h at rt. By contrast, syn-6 led to a mixture of THPs 7b and 7c (65%) with poor
diastereoselectivity after 48 h. This result may be explained by a small difference of stability
between THPs 7b and 7c, as both THPs possess one of the three substituent in an axial
position. Prolonged heating of the mixture of 7b and 7c at 50 °C in the presence of
FeCl3Ÿ6H2O exclusively led to ketone 8 that might result from a 1,5-hydride shift (Scheme 7).
Scheme 7. Access to trisubstituted THPs 12a-12c
Ph
AcO
OH
Ph
Ph
O
FeCl3l6H2O (5 mol %)
Ph
rt, 1 h, CH2Cl2
82%
Ph
7a
(dr > 99:1)
Ph
anti-6
AcO
OH
Ph
Ph
Ph
Ph
Ph
O
FeCl3l6H2O (5 mol %)
Ph
O
rt, 48 h, CH2Cl2
65%
Ph
syn-6
Ph
7b
Ph
7c
(dr = 65:35)
FeCl3l6H2O (5 mol %)
50 °C, 4 h, CH2Cl2
Ph
Ph
Ph
O
8
We also studied the influence of a hydroxyl group at C4 on the outcome of the cyclization. A
mixture of cis- and trans-acetonides 9 was obtained in 5 steps from benzaldehyde and then
treatment with an aqueous 2 M solution of HCl (5 mol %) led to diol anti-10 and to untouched
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acetonide cis-9.17,18 After separation, cis-9 was cleaved into the corresponding syn-diol using
5 equiv of aq. HCl 1 M (83%) (Scheme 8).
6
Scheme 8. Preparation of diols syn-10 and anti-10
7
8
9
aq. HCl 1 M
(5 equiv)
O
O
O
O
OH OH
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Ph
Ph
Ph
Ph
rt, 18 h, THF
83%
cis-9
cis-9
(36%)
aq. HCl 2 M
(5 mol %)
syn-10
0 °C, 3 h, CH2Cl2
Ph
OH OH
O
O
anti-10
(29%)
trans-9
Both diols anti-10 and syn-10 were involved in a cross-metathesis with 1-phenylallyl acetate
and the corresponding allylic acetates anti-11 and syn-11 were isolated in moderate yields
(34% and 30% respectively) (Scheme 9).
OAc
Ph
G-HII (10 mol %)
OH OH
OH OH
OAc
Ph
Ph
Ph
Ph
50 °C, 24 h, CH2Cl2
30%
anti-10
anti-11
OAc
Ph
G-HII (10 mol %)
OH OH
OH OH
OAc
Ph
Ph
50 °C, 24 h, CH2Cl2
34%
syn-10
syn-11
Scheme 9. Synthesis of allylic acetates anti-11 and syn-11
Pleasingly, upon treatment with FeCl3Ÿ6H2O (5 mol %), allylic acetates anti-11 and syn-11
delivered respectively the expected THPs 12a and 12b in excellent yields and diastereomeric
ratio (dr > 99:1) (Scheme 10).
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Scheme 10. Formation of 2,4,6-trisubstituted THPs 12a and 12b
5
6
7
AcO
OH
Ph
FeCl3l6H2O (5 mol %)
Ph
Ph
Ph
O
8
9
rt, 24 h, CH2Cl2
87%
OH
OH
10
11
12
13
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anti-11
12a
(dr > 99:1)
AcO
OH
Ph
Ph
Ph
Ph
O
FeCl3l6H2O (5 mol %)
rt, 48 h, CH2Cl2
94%
OH
OH
syn-11
12b
(dr > 99:1)
Finally, cis-tetrahydropyranone 14 was prepared through the iron-catalyzed cyclization of diol
13.19 The moderate yield of 62% could be explained by a partial degradation of the product
during the reaction (Scheme 11). It should be mentioned that no formation of a dienone
resulting from a dehydration process was observed during the reaction.
Scheme 11. Synthesis of a 2,6-disubstituted tetrahydropyranone
Ph
Ph
Ph
OH
Ph
O
FeCl3l6H2O (5 mol %)
OH
rt, 30 h, CH2Cl2
62%
O
O
14
13
(dr > 99:1)
Synthesis of C2 heteroaryl-tetrahydropyrans
Encouraged by these positive results, we then turned our attention toward the synthesis of
THPs incorporating heteroaryl moieties that could possess the ability of modulating
pharmacological properties. To access the precursor of the cyclization C, a cross-metathesis
between unsaturated alcohols D and 1-phenylallyl acetate was planned. Alcohols D would
result from the addition of the Grignard reagent derived from 1-bromopent-4-ene on a variety
of aldehydes E (Scheme 12).
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Scheme 12. Retrosynthesis of precursors of hydroxy allylic acetates B
5
6
7
AcO
OH
Ph
Ph
AcO
Ph
HetAr
OH
HetAr
HetAr
O
8
9
cross-metathesis
C
B
D
10
11
12
13
14
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Grignard addition
HetAr
O
BrMg
H
E
Initially, the introduction of a pyridyl substituent was examined and alcohol 16a was obtained
by addition of the Grignard reagent, prepared from 1-bromopent-4-ene, on nicotinaldehyde
15a. Disappointingly, when 16a was suggested to the cross-metathesis conditions in the
presence of 1-phenylallyl acetate and Grubbs-Hoveyda second-generation catalyst (G-HII),
no reaction occurred. We hypothesized that the presence of the basic nitrogen on the pyridine
poisoned the ruthenium catalyst thus preventing the reaction from proceeding. To overcome
this difficulty, we recently showed that the introduction of an electron-withdrawing group on
the pyridyl moiety restored the reactivity of the substrate in the cross-metathesis by reducing
the Lewis and/or Brønsted basicity of the nitrogen atom of the N-heteroaryl group.20 As a
consequence, a chlorine atom was introduced on the pyridyl ring and the cross-metathesis
between alcohol 16b and 1-phenylallyl acetate furnished the desired hydroxy allylic acetate
17b in a satisfactory yield of 55% (Scheme 13).16
Scheme 13. Cross-metathesis involving pyridine containing alkenes
OAc
Ph
G-HII (10 mol %)
N
N
N
AcO
OH
Ph
Ph
RMgBr
x
O
O
OH
OH
50 °C, 24 h, CH2Cl2
-78 °C, Et2O
H
17a
16a
15a
OAc
Ph
G-HII (10 mol %)
N
Cl
N
Cl
N
Cl AcO
RMgBr
OH
-78 °C, Et2O
89%
50 °C, 24 h, CH2Cl2
55%
H
17b
15b
16b
R =
MesN NMes
Cl
Ru
Cl
O
G-HII
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The same sequence of reactions was then applied to a wide range of heteroaromatic aldehydes
15c-15i (Table 1). The cross-metathesis tolerated the presence of chloro-
pyrimidines, -(iso)quinolines, -pyrazoles, -imidazoles, -indoles, -pyrroles and in all cases, the
expected products were formed in a moderate but acceptable yield ranging from 46% to 60%
(Table 1).16,21
10
11
12
13
14
15
16
17
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Table 1. Synthesis of allylic acetates 17c-17i
OAc
AcO
OH
Ph
Ph
G-HII (10 mol %)
BrMg
-78 °C, Et2O
HetAr
OH
HetAr
HetAr
O
50 °C, 24 h, CH2Cl2
H
15c-15i
17c-17i
16c-16i
entry
15
16 (yield %)
16c (29%)
17 (yield %)
17c (60%)
N
Cl
1
15c
N
O
Cl
H
2
3
15d
15e
16d (83%)
16e (46%)
17d (49%)
17e (52%)
N
O
Cl
H
N
Cl
O
H
Ph
N
4
5
15f
16f (78%)
16g (95%)
17f (51%)
17g (46%)
Cl
O
H
N
Cl
15g
O
N
MeN
H
Ac
6
7
15h
15i
16h (48%)
16i (61%)
17h (46%)
17i (55%)
N
O
H
Ts
N
O
H
With the hydroxy allylic acetate derivatives in hand, the key cyclization step was next
examined (Table 2). Gratifyingly, when 17b, incorporating a 2-chloro-pyridyl group, was
treated with 5 mol % of FeCl3Ÿ6H2O, the corresponding disubstituted THP 18b was isolated
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in good yield (81%) as a single cis-isomer. Even if the complete conversion of the starting
material was obtained after 2 h, a long reaction time (120 h) was necessary to reach the high
diastereoselectivity in favor of the cis-isomer. Indeed, by monitoring the reaction using
GC/MS, an evolution of the diastereomeric ratio from 66:34 to 99:1 was noticed (Table 2,
entries 1-4).
10
11
12
13
14
15
16
17
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Table 2. Cyclization of hydroxyl acetate 17b
N
Cl AcO
OH
Ph
N
Cl
Ph
FeCl3l6H2O (5 mol %)
O
rt, 120 h, CH2Cl2
17b
18b
81%
entry
time
3 h
cis/trans
66:34
73:27
81:19
99:1
1
2
3
4
7 h
24 h
120 h
This observation suggests an iron-induced re-opening of the cis- and trans-THPs that
proceeds via a zwiterrionic intermediate F (Scheme 14). Due to this equilibration, a
thermodynamic control can be invoked to explain the formation of the more stable cis-isomer
as the major compound. In comparison with our previous results13,14 (see Scheme 5), the
isomerization took a longer reaction time in the presence of N-heteroaromatic substituents
than with alkyl substituents and we hypothesized that, despite the chlorine substituent, the
nitrogen atom could coordinate the iron catalyst thus slowing down the equilibration process
between the cis- and the trans-THPs.22,2324
Scheme 14. FeCl3-induced re-opening of 2,6-disubstituted THPs
Ph
Ph
HetAr
O
HetAr
O
cis-B
trans-B
Ph
Cl3Fe
O
HetAr
F
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The reaction was then extended to the synthesis of 2,6-disubstituted THPs bearing a range of
N-heteroaromatic substituents at C2. The cyclization proceeded smoothly in the presence of a
chloro-pyrimidine or chloro-(iso)-quinolines (Table 3, entries 1-3). Upon treatment with
FeCl3Ÿ6H2O, 17f was transformed into THP 18f bearing a chloro-imidazole moiety with a
moderate yield (57%) after 18 days (Table 3, entry 4). Once again, the long reaction time was
due to difficulties in reaching a high diastereoselectivity. THPs 18g and 18h that respectively
possess a pyrazole and an indole at the C2 position were synthesized in good yields and
excellent diastereomeric ratio (Table 3, entries 5-6). In contrast, the reaction conditions were
not compatible with a pyrrole group as the corresponding THP 18i was obtained with a low
yield of 11%, probably due to the degradation of the starting material in the presence of the
iron catalyst (Table 3, entry 7).
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Table 3. Formation of 2-HetAr THPs 18c-18i
Ph
AcO
OH
Ph
HetAr
O
HetAr
FeCl3l6H O (5 mol %)
2
rt, CH2Cl2
18c-18i
17c-17i
entry
1
17
time
18 (yield)a
N
Cl
Ph
Ph
Ph
N
O
17c
17d
17e
5 d
5 d
5 d
18c (91%)
18d (83%)
18e (76)%
Cl
N
O
2
3
Cl
N
Cl
O
Cl
N
Ph
NPh
4
17f
18 d
18f (57%)
O
Cl
Ph
N
MeN
O
5
6
17g
17h
2 d
2 h
18g (64%)
18h (56%)
Ph
AcN
O
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Ph
NTs
O
7
17i
45 min
18i (11%)
6
7
8
9
a All the THPs were obtained as a single cis-diastereomer.
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Worthy of note, the N-heteroaryl group could be introduced at the allylic position (R2
substituent) through a cross-metathesis between alcohol 16j and allylic acetate 19 (29%).
When 17j was treated with FeCl3Ÿ6H2O, the cyclized product 18j was isolated as a single cis-
isomer with a good yield (72%). Gratifyingly, this cyclization method was compatible with
sophisticated heterocycles such as pyrrolo-pyrimidine (Scheme 15).
Scheme 15. Synthesis of THP incorporating a pyrrolo-pyrimidine motif
N
N
Cl
PhO2SN
NSO2Ph
N
OAc
G-HII (10 mol %)
OH
OH
50 °C, 24 h, CH2Cl2
29%
AcO
N
Cl
19
16j
17j
FeCl3l6H O (5 mol %)
2
72%
rt, 4 d, CH2Cl2
N
N
PhO2SN
Cl
O
18j (dr > 98:2)
The presence of the vinylic substituent at C6 on the THPs offers the opportunity for further
transformations. A dihydroxylation was performed on THP 18b furnishing diol 20 in a 2:1
diastereomeric ratio.25 A subsequent oxidative cleavage delivered aldehyde 21, which was
successfully reduced to alcohol 22 (Scheme 16). These latter could be engaged in further
transformations to get a variety of functionalized compounds.
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Scheme 16. Functionalization of the double bond
5
6
7
N
Cl
H
N
Cl
H
OH
H
H
O
Ph
OsO4, NMO
O
Ph
8
9
rt, H2O/t-BuOH
OH
84%
18b
20
(dr = 2:1)
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NaIO4
rt, THF/buffer pH 7
92%
N
Cl
H
N
Cl
H
O
H
NaBH4
H
O
O
OH
H
rt, EtOH
95%
22
21
Conclusion
A chemo- and diastereoselective iron-catalyzed cyclization was developed to access a wide
variety of tetrahydropyrans possessing a N-heteroaryl at C2, which are attractive scaffolds for
the pharmaceutical industry. The cyclization proceeded in good yields and with excellent
diastereoselectivities in favor of the cis-THP. The use of the cheap and low-toxic FeCl3Ÿ6H2O
as the catalyst as well as the few amount of waste produced during the process makes this
method interesting for industrial purposes. The double bond can be submitted to further
transformations, and thus, this cyclization method could be useful to prepare valuable
functionalized compounds.
Experimental section
General experimental methods. All moisture and oxygen sensitive reactions were carried
out in oven-dried glassware under an argon atmosphere. THF, Et2O and CH2Cl2 were dried
using a purificator. Acetone, petroleum ether (PE), pentane and ethyl acetate (EtOAc) were
used as received. Commercially available reagents were used as received. Reactions run at
room temperature were performed in between 20 °C and 25 °C. Solvent evaporations were
conducted under reduced pressure at temperatures less than 45 °C. TLC were performed on
silica gel plates visualized either with a UV lamp (254 nm) or using a staining solution (p-
anisaldehyde or KMnO4), followed by heating. Column chromatography was carried out
under positive pressure using silica gel (Merck-Kieselgel 60, 230-400) and the indicated
solvents [v/v; used without purification, including petroleum ether (boiling range 40-60 °C)].
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1H-NMR spectra of samples were run at 400 MHz and chemical shifts are given in ppm (δ)
comparatively to the residual solvent signal, which was used as an internal reference (acetone-
d6: δ = 2.05 ppm; CDCl3: δ = 7.26 ppm). Coupling constants (J) are given in Hertz (Hz), and
the following abbreviations are used to describe the signal multiplicity: s (singlet), bs (broad
singlet), d (doublet), t (triplet), q (quadruplet), quint (quintuplet), m (multiplet). 13C-NMR
spectra of samples were run at 100 MHz. Chemical shifts are given in ppm (δ) comparatively
to the residual solvent signal, which was used as an internal reference (acetone-d6: δ = 29.84
ppm; CDCl3: δ = 77.16 ppm). Infrared (IR) spectra were recorded neat (IRFT), wave-
numbers are indicated in cm-1. Low-resolution mass spectra with Electronic Impact (MS-EI)
were recorded on a gas chromatograph-mass spectrometer. High-revolution mass spectra
(HRMS) were performed using ESI and a TOF mass analyzer.
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1-Chloroisoquinoline-7-carbaldehyde (15d). To a stirred solution of 7-bromo-1-
chloroisoquinoline (790 mg, 3.26 mmol, 1.0 equiv) in dry THF (32 mL) at -78 °C was slowly
added a solution of n-BuLi (2.5 M in hexanes, 1.37 mL, 3.42 mmol, 1.05 equiv) and the
resulting mixture was stirred at -78 °C for 40 min. Methylformate (0.606 mL, 9.77 mmol, 3
equiv) was added dropwise and the solution was stirred at -78 °C for 1 h then at rt for another
1 h. The reaction was quenched with ice and a saturated aqueous solution of NH4Cl (20 mL)
was added to the reaction mixture. The phases were separated and the aqueous layer was
extracted with EtOAc (2 × 20 mL). The organic layers were combined, dried over MgSO4,
filtered and the solvents were removed under reduced pressure to give an orange solid, which
was purified by column chromatography (PE/EtOAc = 4:1) to furnish pure aldehyde 15d (398
mg, 64%) as white crystals. These data are in full accordance with those reported in the
literature.26 Rf = 0.42 (PE/EtOAc = 3:1); m.p.: 143-145 °C; IR (Neat): 2871, 1690, 1624,
1549, 1304, 1253, 1224, 1192, 1159, 1135 cm-1; 1H NMR (CDCl3, 400 MHz): δ 10.18 (d, J =
0.8 Hz, 1H), 8.73 (dtapp, J = 1.6 and 0.8 Hz, 1H), 8.36 (d, J = 5.6 Hz, 1H), 8.17 (dd, J = 8.8
and 1.6 Hz, 1H), 7.91 (bd, J = 8.4 Hz, 1H), 7.63 (dd, J = 5.6 and 0.8 Hz, 1H); 13C{1H} NMR
(CDCl3, 100 MHz): δ 191.0, 153.0, 144.5, 140.8, 136.1, 132.3, 128.4, 128.0, 126.6, 120.8;
LRMS (EI) m/z (rel intensity): 193 ([M]·+, 31), 191 ([M]·+, 100), 190 (92), 164 ([M-CHO]+,
19), 162 ([M-CHO]+, 55), 128 (21), 127 ([M-Cl-CHO]·+, 28), 126 (23), 101 (19), 100 (20), 99
(21), 75 (31), 74 (20), 51 (29), 50 (24).
2-Chloroquinoline-3-carbaldehyde (15e). To an ice-cold stirred solution of
diisopropylamine (363 µL, 2.57 mmol, 1.2 equiv) in dry THF (6 mL) was added dropwise n-
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BuLi (2.5 M in hexanes, 941 µL, 2.35 mmol, 1.1 equiv) and the mixture was stirred at 0 °C
for 20 min. The reaction was then cooled down to -78 °C, 2-chloroquinoline (350 mg, 2.14
mmol, 1.0 equiv) was added neat and the resulting mixture was stirred at -78 °C for 35 min.
DMF (273 µL, 3.53 mmol, 1.65 equiv) was slowly added and the solution was stirred at -78
°C for 30 min then at rt for 1 h. Crushed ice was added to quench the reaction, followed by a
saturated aqueous solution of NH4Cl (10 mL) and Et2O (15 mL). The phases were separated
and the aqueous layer was extracted with Et2O (2 × 20 mL). The organic layers were
combined, dried over MgSO4, filtered and the solvents were removed under reduced pressure
to give a yellow liquid, which was purified by column chromatography (PE/EtOAc = 9:1) to
furnish pure aldehyde 15e (277 mg, 68%) as a white solid. These data are in full accordance
with those reported in the literature.27 Rf = 0.38 (PE/EtOAc = 7:1); m.p.: 147-149 °C (lit 146
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°C); IR (Neat): 2871, 1685, 1567, 1488, 1454, 1368, 1331, 1164, 1131, 1042 cm-1; H NMR
(CDCl3, 400 MHz): δ 10.57 (s, 1H), 8.76 (s, 1H), 8.08 (dd, J = 8.8 and 1.2 Hz, 1H), 7.99 (dd,
J = 8.4 and 1.2 Hz, 1H), 7.89 (ddd, J = 8.4, 6.8 and 1.6 Hz, 1H), 7.66 (ddd, J = 8.4, 7.2 and
13
1.2 Hz, 1H); C{1H} NMR (CDCl3, 100 MHz): δ 189.3, 150.3, 149.7, 140.5, 133.8, 129.9,
128.8, 128.3, 126.7, 126.5; LRMS (EI) m/z (rel intensity): 193 ([M]·+, 32), 192 ([M-H]+, 22),
191 ([M]·+, 84), 190 ([M-H]+, 48), 162 ([M-CHO]+, 38), 155 (40), 128 (32), 127 ([M-Cl-
CHO]·+, 100), 101 (45), 100 (22), 76 (22), 75 (50), 74 (25), 51 (40), 50 (39).
2-Chloro-1-phenyl-1H-imidazole (S1). To a stirred solution of 1-phenyl-1H-imidazole (500
mg, 3.47 mmol, 1.0 equiv) in dry THF (30 mL) at -78 °C was added dropwise a solution of n-
BuLi (2.5 M in hexanes, 1.53 mL, 3.82 mmol, 1.1 equiv) and the mixture was stirred at -78
°C for 20 min. A solution of hexachloroethane (2.46 g, 10.40 mmol, 3.0 equiv) in dry THF
(10 mL) was slowly added and the resulting mixture was stirred at -78 °C for 1 h then at rt for
another 1 h. The reaction was quenched with ice and a saturated aqueous solution of NH4Cl
(30 mL) was then added to the reaction mixture. The phases were separated and the aqueous
layer was extracted with EtOAc (2 × 30 mL). The organic layers were combined, dried over
MgSO4, filtered and the solvents were removed under reduced pressure to give an orange
solid, which was purified by column chromatography (PE/EtOAc = 1:1) to furnish pure
chloroimidazole S1 (460 mg, 74%) as off-white crystals. These data are in full accordance
with those reported in the literature.20 Rf = 0.61 (PE/EtOAc = 1:1); m.p.: 53-55 °C; IR
(Neat): 1594, 1495, 1454, 1374, 1307, 1285, 1117, 1088 cm-1; 1H NMR (CDCl3, 400 MHz): δ
7.51-7.42 (m, 3H), 7.36-7.34 (m, 2H), 7.09 (d, J = 1.6 Hz, 1H), 7.05 (d, J = 1.6 Hz, 1H);
13C{1H} NMR (CDCl3, 100 MHz): δ 136.4, 131.8, 129.5 (2C), 128.9, 128.7, 125.8 (2C),
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122.5; LRMS (EI) m/z (rel intensity): 180 ([M]·+, 34), 178 ([M]·+, 100), 153 (20), 151 (66),
5
6
124 (26), 116 (60), 90 (35), 89 (40), 77 (89), 75 (24), 63 (17), 51 (88), 50 (23).
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2-Chloro-1-phenyl-1H-imidazole-5-carbaldehyde (15f). To
a
stirred solution of
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chloroimidazole S1 (210 mg, 1.18 mmol, 1.0 equiv) in dry THF (12 mL) at -78 °C was added
dropwise a solution of n-BuLi (2.5 M in hexanes, 0.49 mL, 1.23 mmol, 1.05 equiv) and the
mixture was stirred at -78 °C for 40 min. Methylformate (0.15 mL, 2.35 mmol, 2 equiv) was
slowly added and the solution was stirred at -78 °C for 1 h then at rt for another 1 h. The
reaction was quenched with ice and a saturated aqueous solution of NH4Cl (15 mL) was
added to the reaction mixture. The phases were separated and the aqueous layer was extracted
with EtOAc (2 × 20 mL). The organic layers were combined, dried over MgSO4, filtered and
the solvents were removed under reduced pressure to give an orange solid, which was purified
by column chromatography (PE/EtOAc = 3:1) to furnish pure aldehyde 15f (193 mg, 79%) as
white crystals. Rf = 0.41 (PE/EtOAc = 2:1); m.p.: 109-111 °C; IR (Neat): 2866, 1670, 1599,
1
1526, 1494, 1430, 1394, 1375, 1361, 1281, 1150 cm-1; H NMR (CDCl3, 400 MHz): δ 9.53
(s, 1H), 7.80 (s, 1H), 7.55-7.50 (m, 3H), 7.31-7.27 (m, 2H); 13C{1H} NMR (CDCl3, 100
MHz): δ 177.4, 140.4, 140.0, 134.2, 133.8, 130.1, 129.5 (2C), 127.3 (2C); LRMS (EI) m/z (rel
intensity): 208 ([M]·+, 11), 206 ([M]·+, 34), 205 (16), 171 ([M-Cl]+, 2), 128 ([M-Ph]+, 4), 116
(19), 89 (17), 78 (100), 77 (34), 51 (37); HRMS (ESI): Calculated for C10H8ClN2O [M+H]+:
207.0320, Found: 207.0320.
3-Chloro-1-methyl-1H-pyrazole-4-carbaldehyde (15g). To dry stirred DMF (0.47 mL, 6.12
mmol, 3.0 equiv) at -15 °C was added dropwise POCl3 (1.33 mL, 14.27 mmol, 7.0 equiv). 3-
Hydroxy-1-methyl-1H-pyrazole (200 mg, 2.04 mmol, 1.0 equiv) was then added and the
solution was refluxed for 2.5 h. After cooling down to rt, the reaction was quenched with
H2O/ice and the mixture was basified with aqueous NaOH 10 M (pH = 10). The phases were
separated and the aqueous layer was further extracted with CH2Cl2 (2 × 30 mL). The organic
layers were combined, dried over MgSO4, filtered and the solvents were removed under
reduced pressure to give a dark brown oily residue, which was purified by column
chromatography (PE/EtOAc = 1:1) to yield aldehyde 15g as a white solid (227 mg, 77%).
These data are in full accordance with those reported in the literature.20 Rf = 0.43 (PE/EtOAc
= 1:1); m.p.: 99-101 °C; IR (Neat): 2818, 1669, 1533, 1416, 1357, 1296, 1177, 1109 cm-1; 1H
13
NMR (CDCl3, 400 MHz): δ 9.78 (s, 1H), 7.87 (s, 1H), 3.90 (d, J = 0.4 Hz, 3H); C{1H}
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NMR (CDCl3, 100 MHz): δ 183.1, 141.8, 134.1, 119.7, 40.2; LRMS (EI) m/z (rel intensity):
146 ([M]·+, 18), 145 ([M-H]+, 34), 144 ([M]·+, 60), 143 ([M-H]+, 100), 51 (20).
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1-Acetyl-1H-indole-3-carbaldehyde (15h). To an ice-cold stirred solution of 1H-indole-3-
carbaldehyde (630 mg, 4.34 mmol, 1.0 equiv), DMAP (53 mg, 0.43 mmol, 0.1 equiv) and
Et3N (1.51 mL, 10.9 mmol, 2.5 equiv) in dry CH2Cl2 (30 mL) was slowly added Ac2O (0.61
mL, 6.51 mmol, 1.5 equiv) and the resulting mixture was stirred at rt for 3 h. After complete
conversion, the reaction was concentrated under reduced pressure to give a beige solid, which
was purified by column chromatography (PE/EtOAc = 1:2) to yield acetamide 15h as a white
solid (709 mg, 87%). These data are in full accordance with those reported in the literature.28
Rf = 0.71 (PE/EtOAc = 1:3); m.p.: 165-167 °C (lit 167-169 °C); IR (Neat): 2841, 1732, 1672,
1606, 1548, 1479, 1446, 1405, 1382, 1370, 1341, 1321, 1254, 1206, 1171, 1126, 1088, 1011
cm-1; 1H NMR (CDCl3, 400 MHz): δ 10.11 (s, 1H), 8.39 (dtapp, J = 7.6 and 0.8 Hz, 1H), 8.26
(ddd, J = 8.0, 1.6 and 0.8 Hz, 1H), 8.05 (s, 1H), 7.44 (tdapp, J = 8.0 and 1.6 Hz, 1H), 7.40
(tdapp, J = 7.6 and 1.6 Hz, 1H), 2.73 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 185.7,
168.7, 136.5, 135.3, 127.0, 126.1, 125.5, 122.8, 122.0, 116.5, 24.0; LRMS (EI) m/z (rel
intensity): 187 ([M]·+, 39), 145 (77), 144 ([M-CH3CO]+, 100), 116 (24), 89 (31), 63 (16).
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1-Tosyl-1H-pyrrole-2-carbaldehyde (15i). To an ice-cold stirred solution of 1H-pyrrole-2-
carbaldehyde (500 mg, 5.26 mmol, 1.0 equiv) in dry THF (35 mL) was slowly added NaH
(60% in mineral oil, 252 mg, 6.31 mmol, 1.2 equiv) and the mixture was stirred at 0 °C for 30
min. TsCl (1.20 g, 6.31 mmol, 1.2 equiv) was then added and the solution was stirred at rt
overnight. Crushed ice was added to quench the reaction, followed by the addition of a
saturated aqueous solution of NH4Cl (25 mL) and water (15 mL). The phases were separated
and the aqueous layer was extracted with Et2O (2 × 35 mL). The organic layers were
combined, dried over MgSO4, filtered and the solvents were removed under reduced pressure
to give a beige solid, which was purified by column chromatography (PE/EtOAc = 4:1) to
furnish N-tosylpyrrole 15i (1.16 g, 89%) as white crystals. These data are in full accordance
with those reported in the literature.29 Rf = 0.34 (PE/EtOAc = 4:1); m.p.: 91-93 °C (lit 92-94
°C); IR (Neat): 1669, 1595, 1538, 1422, 1371, 1248, 1172, 1156, 1140, 1089, 1054, 1012 cm-
1; 1H NMR (CDCl3, 400 MHz): δ 9.95 (s, 1H), 7.78 (dtapp, J = 8.4 and 2.0 Hz, 2H), 7.61 (dd,
J = 3.2 and 2.0 Hz, 1H), 7.30 (bd, J = 8.0 Hz, 2H), 7.14 (dd, J = 3.6 and 2.0 Hz, 1H), 6.39
(tapp, J = 3.6 Hz, 1H), 2.39 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 179.0, 146.0, 135.2,
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([M]·+, 2), 155 ([pTolSO2]+, 16), 94 ([M-pTolSO2]+, 23), 92 (14), 91 ([pTol]+, 100), 65
([pyrrole-H]·+, 31).
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1,3-Diphenylhex-5-en-1-one (S2). To an ice-cold stirred solution of chalcone (1.00 g, 4.80
mmol, 1.0 equiv) and iodine (244 mg, 0.96 mmol, 0.2 equiv) in CH2Cl2 (35 mL) was added
dropwise allyltrimethylsilane (1.07 mL, 6.72 mmol, 1.4 equiv) and the solution was stirred at
rt for 4 h. A saturated aqueous solution of NH4Cl (15 mL) then an aqueous solution of
Na2S2O3 (10 mL) were added and the mixture was stirred for 10 min. The phases were
separated and the aqueous layer was extracted with CH2Cl2 (2 × 20 mL). The organic layers
were combined, dried over MgSO4, filtered and the solvents were removed under reduced
pressure to give a pink residue, which was purified by column chromatography (PE/EtOAc =
20:1) to furnish pure ketone S2 (880 mg, 73%) as a colorless oil. These data are in full
accordance with those reported in the literature.30 Rf = 0.53 (PE/EtOAc = 17:1); IR (Neat):
1
1683, 1639, 1597, 1580, 1494, 1448, 1264, 1201, 1180, 1075, 999, 914 cm-1; H NMR
(CDCl3, 400 MHz): δ 7.91-7.87 (m, 2H), 7.52 (ttapp, J = 8.4 and 1.2 Hz, 1H), 7.44-7.39 (m,
2H), 7.29-7.22 (m, 4H), 7.17 (m, 1H), 5.68 (ddt, J = 17.1, 10.2 and 7.0 Hz, 1H), 5.00 (ddt, J =
16.8, 2.0 and 1.6 Hz, 1H), 4.95 (ddt, J = 10.0, 2.0 and 1.1 Hz, 1H), 3.47 (quint, J = 7.1 Hz,
1H), 3.29 (dd, J = 7.0 and 1.4 Hz, 2H), 2.52-2.40 (m, 2H); 13C{1H} NMR (CDCl3, 100 MHz):
δ 199.0, 144.5, 137.3, 136.4, 133.1, 128.6 (2C), 128.5 (2C), 128.1 (2C), 127.7 (2C), 126.5,
116.9, 44.7, 40.9, 40.8; LRMS (EI) m/z (rel intensity): 250 ([M]·+, 3), 130 (49), 105 ([PhCO]+,
100), 77 ([C6H5]+, 47), 51 (12).
1,3-Diphenylhex-5-en-1-ol (5). To an ice-cold stirred solution of ketone S2 (900 mg, 3.60
mmol, 1.0 equiv) in EtOH (30 mL) was added NaBH4 (163 mg, 4.31 mmol, 1.2 equiv) and
the mixture was stirred at 50 °C for 1 h. The solution was evaporated under reduced pressure
and the residue was taken up in EtOAc (15 mL) and water (15 mL). The phases were
separated and the aqueous layer was extracted with EtOAc (2 × 15 mL). The organic layers
were combined, dried over MgSO4, filtered and the solvents were removed under reduced
pressure to give crude alcohol 5 as a colorless oil. The diastereomers were separated by
column chromatography (PE/EtOAc = 8:1) to furnish pure alcohols anti-5 (308 mg, 34%) and
syn-5 (471 mg, 52%) as colorless oils.
anti-Diastereomer (anti-5). These data are in full accordance with those reported in the
literature.31 Rf = 0.37 (PE/EtOAc = 8:1); IR (Neat): 3377, 1639, 1602, 1493, 1453, 1050, 992
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cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.33-7.19 (m, 10H), 5.66 (ddt, J = 17.1, 10.2 and 7.0 Hz,
1H), 4.95 (m, 1H), 4.91 (m, 1H), 4.33 (bdapp, J = 10.2 Hz, 1H), 3.03 (dtdapp, J = 11.2, 7.3 and
4.1 Hz, 1H), 2.42-2.30 (m, 2H), 2.09 (ddd, J = 14.2, 10.3 and 4.1 Hz, 1H), 1.89-1.82 (m, 2H);
13C{1H} NMR (CDCl3, 100 MHz): δ 145.4, 144.5, 136.8, 128.6 (2C), 128.5 (2C), 128.0 (2C),
127.5, 126.4, 125.6 (2C), 116.3, 71.8, 45.5, 42.4, 41.8; LRMS (EI) m/z (rel intensity): 234
([M-H2O]·+, 2), 130 (13), 107 ([PhCHOH]+, 100), 105 ([PhCO]+, 35), 91 (13), 79 (42), 77
([C6H5]+, 20).
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syn-Diastereomer (syn-5). These data are in full accordance with those reported in the
literature.31 Rf = 0.29 (PE/EtOAc = 8:1); IR (Neat): 3343, 1639, 1602, 1493, 1453, 1028,
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996, 910 cm-1; H NMR (CDCl3, 400 MHz): δ 7.34-7.17 (m, 8H), 7.13-7.10 (m, 2H), 5.54
(ddt, J = 17.2, 10.1 and 7.0 Hz, 1H), 4.90 (m, 1H), 4.88 (m, 1H), 4.46 (btapp, J = 7.2 Hz, 1H),
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2.50 (m, 1H), 2.38-2.25 (m, 2H), 2.19-2.05 (m, 2H), 1.80 (bs, 1H); C{1H} NMR (CDCl3,
100 MHz): δ 144.6, 144.3, 136.5, 128.61 (2C), 128.60 (2C), 127.90, 127.87 (2C), 126.48
(2C), 126.46, 116.4, 73.1, 44.7, 42.4, 41.7; LRMS (EI) m/z (rel intensity): 234 ([M-H2O]·+, 2),
130 (12), 107 ([PhCHOH]+, 100), 105 ([PhCO]+, 37), 91 (16), 79 (45), 77 ([C6H5]+, 24).
4-Phenylbutane-1,2,4-triol (S3). To a stirred solution of 1-phenyl-3-buten-1-ol (2.00 g,
13.50 mmol, 1.0 equiv) and NMO (1.90 g, 16.19 mmol, 1.2 equiv) in H2O (5.5 mL) and
acetone (22 mL) was slowly added a solution of OsO4 (4% in H2O, 843 µL, 0.14 mmol, 0.01
equiv) and the mixture was stirred at rt overnight. The reaction was quenched with an aqueous
solution of Na2S2O3 (25 mL) and EtOAc (60 mL) was added. The phases were separated and
the aqueous layer was extracted with EtOAc (2 × 40 mL). The organic layers were combined,
dried over MgSO4, filtered and the solvents were removed under reduced pressure to give a
brown residue, which was purified by column chromatography (PE/EtOAc = 1:4 to pure
EtOAc) to furnish the desired triol S3 (2.02 g, 82%) as a waxy residue as a 50:50 mixture of
diastereomers.These data are in full accordance with those reported in the literature.32 Rf =
0.33 and 0.26 (EtOAc); IR (Neat): 3321, 1604, 1494, 1453, 1331, 1205, 1101, 1054, 1025,
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910 cm-1; H NMR (CDCl3, 400 MHz): δ 7.26-7.16 (m, 5H), 4.90 (bs, 0.5H), 4.79 (m, 1H),
4.71 (m, 1H), 4.62 (bd, J = 3.6 Hz, 0.5H), 4.42 (bs, 0.5H), 4.27 (bs, 0.5H), 3.94 (bs, 0.5H),
3.80 (bs, 0.5H), 3.48-3.32 (m, 2H), 1.81 (dtapp, J = 14.4 and 9.4 Hz, 0.5H), 1.71-1.58 (m,
1.5H); 13C{1H} NMR (CDCl3, 100 MHz): δ [144.6 and 144.1], [128.6 (2C) and 128.5 (2C)],
[127.7 and 127.4], [125.9 (2C) and 125.7 (2C)], [73.6 and 70.5], [72.0 and 69.3], [66.8 and
66.5], [41.7 and 41.4]; LRMS (EI) m/z (rel intensity): 164 ([M-H2O]·+, 23), 163 (28), 120
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(20), 117 (15), 115 (24), 107 ([PhCHOH]+, 20), 105 ([PhCO]+, 77), 104 ([PhC2H3]·+, 100),
103 (51), 92 (55), 91 (51), 89 (17), 79 (51), 78 (95), 77 ([C6H5]+, 81), 63 (25), 57 (16), 52
(24), 51 (88), 50 (38).
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1-Phenylhex-5-ene-1,3-diol (10). To a stirred solution of triol S3 (1.99 g, 10.92 mmol, 1.0
equiv) in THF/H2O (1:1, 80 mL) was added NaIO4 (9.34 g, 43.68 mmol, 4.0 equiv). The
mixture was stirred at rt for 1 h before adding EtOAc (30 mL) and H2O (30 mL). The phases
were separated and the aqueous layer was extracted with EtOAc (2 × 50 mL). The organic
layers were combined, dried over MgSO4, filtered and the solvents were removed under
reduced pressure to give a yellow oil. The crude aldehyde was diluted in dry THF (50 mL)
and the solution was cooled to -78 °C. Allylmagnesium chloride (2 M in THF, 16.0 mL, 31.96
mmol, 3.2 equiv) was added dropwise and the solution was stirred at -78 °C for 1 h then at rt
for 30 min. The reaction was quenched with ice and a saturated aqueous solution of NH4Cl
(40 mL) was added to the reaction mixture. The phases were separated and the aqueous layer
was extracted with Et2O (2 × 40 mL). The organic layers were combined, dried over MgSO4,
filtered and the solvents were removed under reduced pressure to give an orange oil, which
was purified by column chromatography (PE/EtOAc = 3:1) to furnish diol 10 (1.30 g, 64%) as
a colorless oil as a 50:50 mixture of diastereomers. These data are in full accordance with
those reported in the literature.33 Rf = 0.29 and 0.24 (PE/EtOAc = 2:1); IR (Neat): 3334,
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1643, 1605, 1496, 1454, 1326, 1205, 1060, 996, 915 cm-1; H NMR (CDCl3, 400 MHz): δ
7.35-7.34 (m, 4H), 7.27 (m, 1H), 5.78 (m, 1H), 5.15-5.08 (m, 2H), 5.03 (quintapp, J = 3.8 Hz,
0.5H), 4.91 (ddd, J = 8.8, 4.4 and 1.8 Hz, 0.5H), 3.93 (m, 1H), 3.73 (d, J = 2.0 Hz, 0.5H),
3.37 (d, J = 4.3 Hz, 0.5H), 3.31 (d, J = 2.6 Hz, 0.5H), 2.69 (d, J = 4.0 Hz, 0.5H), 2.28-2.22
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(m, 2H), 1.94-1.75 (m, 2H); C{1H} NMR (CDCl3, 100 MHz): δ [144.6 and 144.5], [134.5
and 134.2], [128.6 (2C) and 128.5 (2C)], [127.7 and 127.4], [125.8 (2C) and 125.6 (2C)],
[118.5 and 118.4], [75.2 and 71.7], [71.6 and 68.1], [44.9 and 44.1], [42.5 and 42.0]; LRMS
(EI) m/z (rel intensity): 174 ([M-H2O]·+, 3), 149 (38), 133 (24), 120 (10), 107 ([PhCHOH]+,
100), 106 (13), 105 ([PhCO]+, 99), 104 ([PhC2H3]·+, 12), 79 (80), 78 (13), 77 ([C6H5]+, 47),
68 (19), 67 (20), 51 (13).
4-Allyl-2,2-dimethyl-6-phenyl-1,3-dioxane (9).To a stirred solution of diol 10 (1.25 g, 6.50
mmol, 1.0 equiv) and 2,2-dimethoxypropane (8.06 mL, 65.02 mmol, 10.0 equiv) in CH2Cl2
(35 mL) was added PPTS (163 mg, 0.65 mmol, 0.1 equiv) and the solution was stirred at rt for
20 h. A saturated aqueous solution of NH4Cl (15 mL) and H2O (10 mL) were added, the
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phases were separated and the aqueous layer was extracted with CH2Cl2 (2 × 30 mL). The
organic layers were combined, dried over MgSO4, filtered and the solvents were removed
under reduced pressure to give a pale yellow oil, which was purified by column
chromatography (PE/EtOAc = 14:1) to furnish acetonide 9 (1.31 g, 87%) as a colorless oil as
a 50:50 mixture of diastereomers. Rf = 0.50 (PE/EtOAc = 14:1); IR (Neat): 1643, 1606, 1496,
1451, 1378, 1252, 1225, 1200, 1168, 1100, 1071, 1019, 960, 913 cm-1; 1H NMR (CDCl3, 400
MHz): δ 7.39-7.32 (m, 4H), 7.26 (m, 1H), 5.83 (m, 1H), 5.15-5.04 (m, 2H), 4.88 (m, 1H),
4.04 (m, 1H), 2.38 (m, 1H), 2.23 (m, 1H), 1.96 (m, 1H), 1.75 (dtapp, J = 13.2 and 2.5 Hz,
0.5H), 1.56 (s, 1.5H), 1.52 (s, 1.5H), 1.46 (s, 1.5H), 1.45 (s, 1.5H), 1.45 (dt, J = 13.3 and 11.5
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Hz, 0.5H); C{1H} NMR (CDCl3, 100 MHz): δ [142.7 and 142.5], [134.4 and 134.1], 128.5
(2C), [127.7 and 127.5], [126.1 (2C) and 126.0 (2C)], [117.4 and 117.2], [100.9 and 99.1],
[71.7 and 68.7], [68.9 and 66.5], [40.9 and 40.3], [39.6 and 39.0], [30.4 and 25.3], [24.9 and
19.9]; LRMS (EI) m/z (rel intensity): 217 ([M-CH3]+, 7), 174 ([M-acetone]·+, 17), 157 ([M-
acetone-OH]+, 27), 133 (32), 129 (33), 115 (41), 107 (68), 105 ([PhCO]+, 100), 104
([PhC2H3]·+, 37), 103 (18), 91 (44), 79 (25), 78 (20), 77 ([C6H5]+, 34), 68 (93), 67 (50), 59
(62); HRMS (ESI): Calculated for C15H20O2Na [M+Na]+: 255.1356, Found: 255.1356
4-Allyl-2,2-dimethyl-6-phenyl-1,3-dioxane (cis-9). To an ice-cold stirred solution of
acetonide 9 (600 mg, 2.58 mmol, 1.0 equiv) in CH2Cl2 (200 mL) was added a 2 M aqueous
solution of HCl (65 µL, 0.13 mmol, 0.05 equiv) and the solution was vigorously stirred at 0
°C for 3 h. A saturated aqueous solution of Na2CO3 (15 mL) and H2O (85 mL) were added,
the phases were separated and the aqueous layer was extracted with CH2Cl2 (2 × 100 mL).
The organic layers were combined, dried over MgSO4, filtered and the solvents were removed
under reduced pressure to give a yellow oil, which was purified by column chromatography
(PE/EtOAc = 14:1 then 2:1) to furnish pure acetonide cis-9 (214 mg, 36%) and diol anti-10
(145 mg, 29%) as colorless oils. Rf = 0.50 (PE/EtOAc = 14:1); IR (Neat): 1643, 1605, 1496,
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1452, 1378, 1252, 1198, 1167, 1101, 1071, 1046, 961, 913 cm-1; H NMR (CDCl3, 400
MHz): δ 7.42-7.35 (m, 4H), 7.29 (ttapp, J = 6.8 and 2.0 Hz, 1H), 5.86 (dddd, J = 17.2, 10.3, 7.6
and 6.6 Hz, 1H), 5.12 (m, 1H), 5.09 (m, 1H), 4.92 (dd, J = 11.7 and 2.8 Hz, 1H), 4.07 (dtd, J
= 11.5, 6.3 and 2.4 Hz, 1H), 2.40 (dttapp, J = 14.0, 6.3 and 1.5 Hz, 1H), 2.22 (dddt, J = 14.1,
7.6, 6.7 and 1.4 Hz, 1H), 1.78 (dtapp, J = 13.2 and 2.5 Hz, 1H), 1.59 (s, 3H), 1.55 (s, 3H), 1.48
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(dtapp, J = 13.1 and 11.6 Hz, 1H); C{1H} NMR (CDCl3, 100 MHz): δ 142.5, 134.1, 128.5
(2C), 127.7, 126.0 (2C), 117.4, 99.1, 71.6, 68.9, 40.9, 39.0, 30.4, 19.9; LRMS (EI) m/z (rel
intensity): 217 ([M-CH3]+, 10), 174 ([M-acetone]·+, 1), 157 ([M-acetone-OH]+, 17), 133 (17),
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129 (19), 115 (29), 105 ([PhCO]+, 72), 104 ([PhC2H3]·+, 100), 103 (50), 91 (37), 79 (23), 78
(78), 77 ([C6H5]+, 62), 68 (29), 67 (24), 63 (17), 59 (30), 58 (38), 52 (22), 51 (71), 50 (33);
HRMS (ESI): Calculated for C15H20O2Na [M+Na]+: 255.1356, Found: 255.1357
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1-Phenylhex-5-ene-1,3-diol (anti-10). These data are in full accordance with those reported
in the literature. 34 Rf = 0.24 (PE/EtOAc = 2:1); IR (Neat): 3346, 1641, 1603, 1494, 1452,
1323, 1207, 1050, 994 cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.33 (dapp, J = 4.3 Hz, 4H), 7.26
(m, 1H), 5.77 (ddt, J = 16.0, 11.6 and 6.8 Hz, 1H), 5.13-5.07 (m, 2H), 5.01 (bdapp, J = 8.0 Hz,
1H), 3.90 (bqapp, J = 7.1 Hz, 1H), 3.72 (bdapp, J = 2.8 Hz, 1H), 3.01 (bs, 1H), 2.26-2.22 (m,
2H), 1.92-1.78 (m, 2H); 13C{1H} NMR (CDCl3, 100 MHz): δ 144.6, 134.5, 128.5 (2C), 127.3,
125.6 (2C), 118.2, 71.4, 68.0, 44.2, 42.0; LRMS (EI) m/z (rel intensity): 174 ([M-H2O]·+, 2),
156 ([M-2H2O]·+, 19), 115 ([M-Ph]+, 19), 107 ([PhCHOH]+, 32), 106 (28), 105 ([PhCO]+,
100), 104 ([PhC2H3]·+, 62), 103 (42), 91 (30), 79 (46), 78 (59), 77 ([C6H5]+, 89), 76 (15), 63
(19), 52 (22), 51 (86), 50 (41).
1-Phenylhex-5-ene-1,3-diol (syn-10). To an ice-cold stirred solution of acetonide cis-9 (200
mg, 0.86 mmol, 1.0 equiv) in THF (15 mL) was added a 1 M aqueous solution of HCl (4.3
mL, 4.30 mmol, 5.0 equiv) and the solution was stirred at rt. After 18 h, a saturated aqueous
solution of Na2CO3 (5 mL) and H2O (5 mL) were added, the phases were separated and the
aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The organic layers were combined,
dried over MgSO4, filtered and the solvents were removed under reduced pressure to give a
yellow oil, which was purified by column chromatography (PE/EtOAc = 2:1) to furnish diol
syn-10 (137 mg, 83%) as a colorless oil. These data are in full accordance with those reported
in the literature.34 Rf = 0.29 (PE/EtOAc = 2:1); IR (Neat): 3262, 1640, 1494, 1446, 1366,
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1332, 1287, 1202, 1114, 1097, 1065, 1033, 1003, 910 cm-1; H NMR (CDCl3, 400 MHz): δ
7.33 (dapp, J = 4.4 Hz, 4H), 7.26 (m, 1H), 5.76 (ddt, J = 17.6, 9.6 and 7.2 Hz, 1H), 5.11-5.05
(m, 2H), 4.85 (ddd, J = 9.4, 4.0 and 2.0 Hz, 1H), 4.08 (d, J = 2.1 Hz, 1H), 3.91 (m, 1H), 3.64
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(d, J = 2.7 Hz, 1H), 2.21 (ddtapp, J = 7.2, 6.0 and 1.2 Hz, 2H), 1.83-1.73 (m, 2H); C{1H}
NMR (CDCl3, 100 MHz): δ 144.5, 134.2, 128.5 (2C), 127.6, 125.8 (2C), 118.2, 75.0, 71.6,
44.7, 42.4; LRMS (EI) m/z (rel intensity): 156 ([M-2H2O]·+, 15), 133 (18), 115 ([M-Ph]+,13),
107 ([PhCHOH]+, 39), 106 (25), 105 ([PhCO]+, 100), 104 ([PhC2H3]·+, 43), 103 (30), 91 (25),
79 (61), 78 (44), 77 ([C6H5]+, 87), 68 (15), 52 (16), 51 (58), 50 (27).
Grignard reagent S4. The Grignard reagent S4 was synthesized by reacting 5-bromopentene
(1.0 equiv) with magnesium turnings (2.0 equiv) and one crystal of iodine in refluxing dry
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Et2O (0.5 M) for 1.5 h. The mixture was then cooled down to rt and decantated to furnish a
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General Procedure 1: Synthesis of alcohols 16b-16j. To a stirred solution of aldehyde (1.0
equiv) in dry Et2O (0.3 M) at -78 °C was added dropwise a solution of 4-pentenylmagnesium
bromide S4 (1.5 to 2.0 equiv) in Et2O. The mixture was stirred at -78 °C for 30 min then at rt
for 1.5 h. The reaction was quenched with ice and a saturated aqueous solution of NH4Cl (20
mL) was added to the reaction mixture. The phases were separated and the aqueous layer was
further extracted with EtOAc (2 × 30 mL). The organic layers were combined, dried over
MgSO4, filtered and the solvents were removed under reduced pressure to give an orange oily
residue, which was purified by column chromatography to yield the desired alcohol.
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1-(2-Chloropyridin-3-yl)hex-5-en-1-ol (16b). Prepared according to the General Procedure
1 using 2-chloro-3-pyridinecarboxaldehyde 15b (400 mg, 2.83 mmol). The crude product was
purified by column chromatography (CH2Cl2/EtOAc = 5:1) to furnish pure alcohol 16b (535
mg, 89%) as a colorless oil. Rf = 0.48 (CH2Cl2/EtOAc = 5:1); IR (Neat): 3334, 1640, 1567,
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1407, 1337, 1260, 1185, 1116, 1058, 993 cm-1; H NMR (CDCl3, 400 MHz): δ 8.17 (dd, J =
4.8 and 2.0 Hz, 1H), 7.91 (ddd, J = 7.6, 2.0 and 0.4 Hz, 1H), 7.22 (ddd, J = 7.6, 4.8 and 0.4
Hz, 1H), 5.76 (ddt, J = 17.2, 10.0 and 6.4 Hz, 1H), 5.03 (dtapp, J = 7.6 and 4.0 Hz, 1H), 4.97
(dqapp, J = 16.8 and 1.6 Hz, 1H), 4.92 (ddt, J = 10.0, 2.0 and 1.2 Hz, 1H), 3.38 (d, J = 4.0 Hz,
1H), 2.14-2.00 (m, 2H), 1.76 (m, 1H), 1.68-1.43 (m, 3H); 13C{1H} NMR (CDCl3, 100 MHz):
δ 148.6, 148.0, 139.5, 138.4, 136.5, 123.0, 114.9, 69.7, 36.9, 33.4, 24.9; LRMS (EI) m/z (rel
intensity): 211 ([M]·+, 1), 168 (21), 155 (17), 144 ([M-C5H9]+, 32), 142 ([M-C5H9]+, 100), 139
(15), 106 (63), 78 (51), 51 (24); HRMS (ESI): Calculated for C11H15ClNO [M+H]+: 212.0837,
Found: 212.0837.
1-(4,6-Dichloropyrimidin-5-yl)hex-5-en-1-ol (16c). Prepared according to the General
Procedure 1 using 4,6-dichloropyrimidine-5-carboxaldehyde 15c (400 mg, 2.26 mmol). The
crude product was purified by column chromatography (PE/EtOAc = 6:1) to furnish pure
alcohol 16c (162 mg, 29%) as a colorless oil. Rf = 0.36 (PE/EtOAc = 6:1); IR (Neat): 3407,
1640, 1514, 1415, 1331, 1225, 1132, 1071, 993 cm-1; 1H NMR (CDCl3, 400 MHz): δ 8.65 (s,
1H), 5.76 (ddt, J = 16.8, 10.0 and 6.8 Hz, 1H), 5.30 (bt, J = 6.8 Hz, 1H), 5.00 (dqapp, J = 17.2
and 2.0 Hz, 1H), 4.96 (ddt, J = 10.4, 2.4 and 1.6 Hz, 1H), 2.82 (bs, 1H, OH), 2.14-2.03 (m,
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(CDCl3, 100 MHz): δ 160.7 (2C), 156.4, 137.9, 133.4, 115.4, 70.3, 34.2, 33.2, 25.1; LRMS
(EI) m/z (rel intensity): 228 ([M-H2O]·+, 1), 213 ([M-Cl]+, 4), 211 ([M-Cl]+, 4), 181 ([M-
C5H9]+, 5), 179 ([M-C5H9]+, 30), 177 ([M-C5H9]+, 48), 141 (18), 86 (27), 67 (17), 55 (17), 54
(100); HRMS (ESI): Calculated for C10H13Cl2N2O [M+H]+: 247.0399, Found: 247.0400
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1-(1-Chloroisoquinolin-7-yl)hex-5-en-1-ol (16d). Prepared according to the General
Procedure 1 using aldehyde 15d (350 mg, 1.83 mmol). The crude product was purified by
column chromatography (PE/EtOAc = 6:1) to furnish pure alcohol 16d (395 mg, 83%) as a
colorless oil. Rf = 0.40 (PE/EtOAc = 4:1); IR (Neat): 3337, 2858, 1589, 1551, 1438, 1413,
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1305, 1258, 1227, 1161, 1066, 993 cm-1; H NMR (CDCl3, 400 MHz): δ 8.23-8.21 (m, 2H),
7.81 (bd, J = 8.4 Hz, 1H), 7.76 (dd, J = 8.8 and 2.0 Hz, 1H), 7.56 (dd, J = 5.6 and 0.8 Hz,
1H), 5.77 (ddt, J = 17.2, 10.0 and 6.4 Hz, 1H), 5.00 (dqapp, J = 17.2 and 1.6 Hz, 1H), 4.95
(ddt, J = 10.0, 2.0 and 1.2 Hz, 1H), 4.93 (bdd, J = 7.6 and 5.6 Hz, 1H), 2.43 (bs, 1H, OH),
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2.10 (qtapp, J = 6.8 and 1.2 Hz, 2H), 1.93-1.76 (m, 2H), 1.58 (m, 1H), 1.43 (m, 1H); C{1H}
NMR (CDCl3, 100 MHz): δ 151.6, 145.7, 141.4, 138.4, 137.4, 129.7, 127.5, 126.9, 123.0,
120.7, 115.1, 74.3, 38.7, 33.6, 25.1; LRMS (EI) m/z (rel intensity): 263 ([M]·+, 2), 261 ([M]·+,
7), 245 ([M-H2O]·+, 9), 243 ([M-H2O]·+, 25), 218 (35), 207 (14), 205 (46), 204 (16), 202 (45),
194 ([M-C5H9]+, 27), 192 ([M-C5H9]+, 91), 191 ([1-chloroisoquinolineC2H3]·+, 17), 190 (22),
189 ([1-chloroisoquinolineC2H3]·+, 34), 166 (41), 164 (25), 129 ([isoquinoline]·+, 13), 128
([isoquinoline-H]+, 100), 101 (20), 77 ([C6H5]+, 18); HRMS (ESI): Calculated for
C15H17ClNO [M+H]+: 262.0993, Found: 262.0997
1-(2-Chloroquinolin-3-yl)hex-5-en-1-ol (16e). Prepared according to the General
Procedure 1 using aldehyde 15e (230 mg, 1.20 mmol). The crude product was purified by
column chromatography (Pentane/EtOAc = 6:1) to furnish pure alcohol 16e (143 mg, 46%) as
a colorless oil. Rf = 0.43 (PE/EtOAc = 6:1); IR (Neat): 3343, 3065, 1639, 1619, 1589, 1563,
1491, 1397, 1325, 1205, 1137, 1070, 1037 cm-1; 1H NMR (CDCl3, 400 MHz): δ 8.28 (s, 1H),
7.90 (dd, J = 8.8 and 1.2 Hz, 1H), 7.69 (dd, J = 8.0 and 1.6 Hz, 1H), 7.63 (ddd, J = 8.4, 6.8
and 1.6 Hz, 1H), 7.47 (ddd, J = 8.0, 6.8 and 1.2 Hz, 1H), 5.76 (ddt, J = 17.2, 10.4 and 6.8 Hz,
1H), 5.15 (bdt, J = 8.0 and 3.2 Hz, 1H), 4.98 (dqapp, J = 17.2 and 1.6 Hz, 1H), 4.92 (ddt, J =
10.0, 2.0 and 1.2 Hz, 1H), 3.53 (d, J = 3.6 Hz, 1H, OH), 2.16-2.01 (m, 2H), 1.86 (m, 1H),
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1.72-1.50 (m, 3H); C{1H} NMR (CDCl3, 100 MHz): δ 148.8, 146.6, 138.4, 137.0, 135.8,
130.2, 127.8, 127.7, 127.4, 127.1, 114.9, 70.0, 37.2, 33.4, 25.1; LRMS (EI) m/z (rel intensity):
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261 ([M]·+, 7), 245 ([M-H2O]·+, 15), 243 ([M-H2O]·+, 45), 218 (18), 207 (17), 206 (18), 205
(28), 204 (25), 202 (62), 194 ([M-C5H9]+, 29), 192 ([M-C5H9]+, 100), 191
([chloroquinolineC2H3]·+, 28), 190 (21), 189 ([chloroquinolineC2H3]·+, 68), 180 (16), 167
(41), 166 (31), 156 (70), 154 (20), 140 (22), 128 ([quinoline-H]+, 81), 101 (38), 77 ([C6H5]+,
25) 75 (20), 51 (20); HRMS (ESI): Calculated for C15H17ClNO [M+H]+: 262.0993, Found:
262.0996
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1-(2-Chloro-1-phenyl-1H-imidazol-5-yl)hex-5-en-1-ol (16f). Prepared according to the
General Procedure 1 using aldehyde 15f (310 mg, 1.50 mmol). The crude product was
purified by column chromatography (PE/EtOAc = 3:1) to furnish pure alcohol 16f (322 mg,
78%) as white crystals. Rf = 0.39 (PE/EtOAc = 3:1); m.p.: 100-102 °C; IR (Neat): 3179,
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1597, 1563, 1498, 1454, 1395, 1279, 1073, 987 cm-1; H NMR (CDCl3, 400 MHz): δ 7.52-
4.49 (m, 3H), 7.31 (bs, 2H), 6.92 (d, J = 0.4 Hz, 1H), 5.70 (ddt, J = 17.2, 10.4 and 6.4 Hz,
1H), 4.93 (dqapp, J = 17.2 and 2.0 Hz, 1H), 4.90 (ddt, J = 10.0, 2.0 and 1.6 Hz, 1H), 4.33 (bt, J
= 7.2 Hz, 1H), 3.08 (bs, 1H, OH), 1.98 (bqapp, J = 6.8 Hz, 2H), 1.79-1.66 (m, 2H), 1.47 (m,
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1H), 1.35 (m, 1H); C{1H} NMR (CDCl3, 100 MHz): δ 138.3, 138.0, 134.9, 133.0, 129.7
(2C), 129.5 (2C), 128.2, 125.3, 115.0, 64.9, 35.2, 33.3, 25.1; LRMS (EI) m/z (rel intensity):
276 ([M]·+, 4), 260 ([M-H2O]·+, 5), 258 ([M-H2O]·+, 16), 241 ([M-Cl]+, 3), 219 (31), 218 (14),
217 (96), 209 ([M-C5H9]+, 19), 207 ([M-C5H9]+, 60), 179 (25), 156 (31), 138 (30), 129 (17),
78 (20), 77 ([C6H5]+, 100), 51 (43); HRMS (ESI): Calculated for C15H18ClN2O [M+H]+:
277.1102, Found: 277.1107
1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)hex-5-en-1-ol (16g). Prepared according to the
General Procedure 1 using aldehyde 15g (280 mg, 1.94 mmol). The crude product was
purified by column chromatography (PE/EtOAc = 1:1) to furnish pure alcohol 16g (394 mg,
95%) as a yellow oil. Rf = 0.23 (PE/EtOAc = 1:1); IR (Neat): 3372, 3077, 1640, 1557, 1407,
1315, 1175, 1068, 1001, 910 cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.27 (s, 1H), 5.76 (ddt, J =
16.8, 10.0 and 6.8 Hz, 1H), 4.98 (dqapp, J = 17.2 and 1.6 Hz, 1H), 4.92 (ddt, J = 10.0, 2.0 and
1.2 Hz, 1H), 4.63 (dd, J = 7.6 and 6.4 Hz, 1H), 3.78 (s, 3H), 2.55 (bs, 1H, OH), 2.06 (qtapp, J
= 7.2 and 1.6 Hz, 2H), 1.82-1.66 (m, 2H), 1.50 (m, 1H), 1.38 (m, 1H); 13C{1H} NMR (CDCl3,
100 MHz): δ 138.5, 136.6, 129.6, 122.4, 114.8, 65.5, 39.6, 37.1, 33.5, 24.9; LRMS (EI) m/z
(rel intensity): 198 ([M-H2O]·+, 10), 196 ([M-H2O]·+, 32), 157 (34), 155 (100), 147 ([M-
C5H9]+, 15), 145 ([M-C5H9]+, 53), 144 (22), 143 (19), 142 (62), 129 (21), 128 (16), 120 (30),
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119 (37), 116 (16), 114 (38), 92 (17), 78 (17), 77 (19), 65 (17), 51 (20); HRMS (ESI):
Calculated for C10H16ClN2O [M+H]+: 215.0946, Found: 215.0945
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1-(3-(1-Hydroxyhex-5-en-1-yl)-1H-indol-1-yl)ethanone (16h). Prepared according to the
General Procedure 1 using aldehyde 15h (300 mg, 1.60 mmol). The crude product was
purified by column chromatography (PE/EtOAc = 3:1) to furnish pure alcohol 16h (198 mg,
48%) as a yellow oil. Rf = 0.46 (PE/EtOAc = 2:1); IR (Neat): 3400, 1689, 1605, 1450, 1384,
1329, 1241, 1218, 1126, 1007, 935 cm-1; 1H NMR (CDCl3, 400 MHz): δ 8.42 (d, J = 8.0 Hz,
1H), 7.64 (ddd, J = 7.6, 1.2 and 0.8 Hz, 1H), 7.36 (ddd, J = 8.4, 7.6 and 1.2 Hz, 1H), 7.30 (s,
1H), 7.28 (ddd, J = 8.0, 7.2 and 1.2 Hz, 1H), 5.80 (ddt, J = 17.2, 10.4 and 6.8 Hz, 1H), 5.01
(dqapp, J = 17.2 and 1.6 Hz, 1H), 4.98-4.95 (m, 2H), 2.55 (s, 3H), 2.15-2.09 (m, 3H), 1.97-
1.90 (m, 2H), 1.62 (m, 1H), 1.51 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 168.8, 138.6,
136.4, 128.7, 126.3, 125.5, 123.7, 121.7, 119.8, 116.9, 115.0, 68.0, 36.9, 33.6, 25.2, 24.1;
LRMS (EI) m/z (rel intensity): 257 ([M]·+, 4), 239 ([M-H2O]·+, 21), 198 (24), 156 (100), 146
(27), 143 (16), 129 (49), 128 (22), 118 (21); HRMS (ESI): Calculated for C16H19NO2Na
[M+Na]+: 280.1308, Found: 280.1308
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1-(1-Tosyl-1H-pyrrol-2-yl)hex-5-en-1-ol (16i). Prepared according to the General
Procedure 1 using aldehyde 15i (380 mg, 1.52 mmol). The crude product was purified by
column chromatography (PE/EtOAc = 4:1) to furnish pure alcohol 16i (298 mg, 61%) as a
colorless oil. Rf = 0.51 (PE/EtOAc = 4:1); IR (Neat): 3414, 1640, 1597, 1364, 1173, 1150,
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1089, 1055, 910 cm-1; H NMR (CDCl3, 400 MHz): δ 7.66 (dtapp, J = 8.4 and 2.0 Hz, 2H),
7.29-7.27 (m, 3H), 6.26 (ddd, J = 3.2, 1.6 and 0.4 Hz, 1H), 6.23 (td, J = 3.2 and 0.4 Hz, 1H),
5.73 (ddt, J = 16.8, 10.0 and 6.8 Hz, 1H), 4.94 (dqapp, J = 16.8 and 2.0 Hz, 1H), 4.91 (ddt, J =
10.0, 2.0 and 1.2 Hz, 1H), 4.82 (m, 1H), 2.85 (d, J = 4.0 Hz, 1H), 2.39 (s, 3H), 2.06-1.91 (m,
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2H), 1.87-1.72 (m, 2H), 1.48 (m, 1H), 1.37 (m, 1H); C{1H} NMR (CDCl3, 100 MHz): δ
145.2, 138.5, 138.2, 136.3, 130.1 (2C), 126.6 (2C), 123.4, 114.7, 112.3, 111.6, 65.1, 34.6,
33.3, 25.3, 21.7; LRMS (EI) m/z (rel intensity): 301 ([M-H2O]·+, 6), 260 (44), 155
([pTolSO2]+, 30), 105 (16), 104 (17), 92 (15), 91 ([pTol]+, 100), 65 ([pyrrole-H]·+, 36);
HRMS (ESI): Calculated for C17H21NO3SNa [M+Na]+: 342.1134, Found: 342.1133
1-Phenylhex-5-en-1-ol (16j). Prepared according to the General Procedure 1 using
benzaldehyde (508 mg, 4.79 mmol). The crude product was purified by column
chromatography (PE/EtOAc = 5:1) to furnish pure alcohol 16j (673 mg, 80%) as a colorless
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oil. These data are in full accordance with those reported in the literature.35 Rf = 0.35
(PE/EtOAc = 6:1); IR (Neat): 3344, 2934, 2860, 1640, 1493, 1454, 1201, 1062, 1027, 993
cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.38-7.26 (m, 5H), 5.79 (ddt, J = 17.2, 10.4 and 6.4 Hz,
1H), 5.00 (ddt, J = 17.2, 2.4 and 1.6 Hz, 1H), 4.95 (ddt, J = 10.0, 2.4 and 1.2 Hz, 1H), 4.66
(dd, J = 7.2 and 5.6 Hz, 1H), 2.08 (qtapp, J = 7.2 and 1.2 Hz, 2H), 2.04 (s, 1H, OH), 1.86-1.68
(m, 2H), 1.53 (m, 1H), 1.39 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 144.9, 138.7,
128.5 (2C), 127.6, 126.0 (2C), 114.8, 74.6, 38.6, 33.7, 25.2; LRMS (EI) m/z (rel intensity):
176 ([M]·+, 2), 158 ([M-H2O]·+, 17), 133 (22), 120 (21), 117 ([M-H2O-C3H5]+, 53), 115 (28),
107 ([M-C5H9]+, 100), 105 (19), 104 ([PhC2H3]·+, 38), 91 (21), 79 (71), 77 ([C6H5]+, 40), 51
(16).
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1-(4-Chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)allyl acetate (19). To an
ice-cold stirred solution of 1-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-5-
yl)prop-2-en-1-ol (70 mg, 0.20 mmol, 1.0 equiv), DMAP (2.4 mg, 0.02 mmol, 0.1 equiv) and
Et3N (70 µL, 0.50 mmol, 2.5 equiv) in dry CH2Cl2 (1.5 mL) was slowly added Ac2O (28 µL,
0.30 mmol, 1.5 equiv) and the resulting mixture was stirred at 0 °C for 1 h. After complete
conversion, the reaction was concentrated under reduced pressure to give a yellow solid,
which was purified by column chromatography on neutralized silica gel (PE/EtOAc = 2:1) to
yield allylic acetate 19 as white crystals (78 mg, 99%). Rf = 0.38 (PE/EtOAc = 2:1); m.p.:
155-157 °C; IR (Neat): 1738, 1591, 1542, 1436, 1384, 1229, 1155, 1092, 1017, 935 cm-1; 1H
NMR (CDCl3, 400 MHz): δ 8.75 (s, 1H), 8.22 (m, 2H), 7.78 (d, J = 0.8 Hz, 1H), 7.66 (tt, J =
7.6 and 2.0 Hz, 1H), 7.55 (m, 2H), 6.71 (dqapp, J = 5.6 and 1.2 Hz, 1H), 6.13 (ddd, J = 17.2,
10.4 and 6.0 Hz, 1H), 5.40 (dtapp, J = 10.8 and 1.2 Hz, 1H), 5.38 (ddd, J = 17.2, 1.2 and 0.8
Hz, 1H), 2.12 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 169.7, 152.9, 152.8, 151.7, 137.2,
135.2, 133.8, 129.5 (2C), 128.6 (2C), 126.0, 119.1, 117.6, 116.7, 68.3, 21.2; LRMS (EI) m/z
(rel intensity): 333 ([M-AcOH]·+, 4), 331 ([M-AcOH]·+, 13), 208 (28), 191 (15), 190 (29), 141
([PhSO2]+, 28), 78 (13), 77 ([C6H5]+, 100), 51 (27); HRMS (ESI): Calculated for
C17H14ClN3O4SNa [M+Na]+: 414.0286, Found: 414.0286.
General Procedure 2: Synthesis of hydroxy allylic acetates 3, 6, 11, 17b-17j by cross-
metathesis. To a stirred solution of alcohol (1.0 equiv) and 1-phenylallyl acetate S536 or
allylic acetate 19 (3.0 equiv) in dry CH2Cl2 (0.7 M) in a sealed tube under argon was added
Grubbs-Hoveyda II catalyst (10 mol %). The mixture was stirred at 50 °C for 24 h, cooled
down to rt and the solvent was removed under reduced pressure to give a dark green oil,
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which was purified by column chromatography on neutralized silica gel to yield the desired
hydroxy allylic acetate.
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(E)-7-Hydroxy-1,7-diphenylhept-2-en-1-yl acetate (3). Prepared according to the General
Procedure 2 using alcohol 16j (200 mg, 1.14 mmol) and allylic acetate S5. The product was
purified by column chromatography (PE/EtOAc = 5:1) to furnish pure olefin 3 (201 mg, 55%)
as a greenish oil as a 50:50 mixture of diastereomers. Rf = 0.25 (PE/EtOAc = 5:1); IR (Neat):
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3413, 1733, 1603, 1494, 1453, 1370, 1232, 1018, 964 cm-1; H NMR (CDCl3, 400 MHz): δ
7.38-7.27 (m, 10H), 6.22 (d, J = 6.4 Hz, 1H), 5.72 (m, 1H), 5.63 (ddd, J = 15.2, 6.4 and 0.8
Hz, 1H), 4.64 (dd, J = 7.2 and 5.6 Hz, 1H), 2.09 (s, 1.5H), 2.08 (s, 1.5H), 2.11-2.03 (m, 3H),
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1.84-1.65 (m, 2H), 1.53 (m, 1H), 1.39 (m, 1H); C{1H} NMR (CDCl3, 100 MHz): δ 170.2,
144.9, [139.77 and 139.76], [134.4 and 134.3], [128.72 and 128.70], 128.6 (2C), 128.5 (2C),
128.0, [127.60 and 127.59], [127.0 (2C) and 126.9 (2C)], [126.0 (2C) and 125.9 (2C)], [76.37
and 76.36], [74.41 and 74.37], [38.54 and 38.53], [32.09 and 32.08], [25.1 and 25.0], 21.4;
LRMS (EI) m/z (rel intensity): 264 ([M-AcOH]·+, 12), 130 (16), 129, (18), 117 (12), 115 (17),
105 (22), 104 ([PhC2H3]·+, 100), 91 (21), 77 ([C6H5]+, 15); HRMS (ESI): Calculated for
C21H24O3Na [M+Na]+: 347.1618, Found: 347.1618.
(E)-7-Hydroxy-1,5,7-triphenylhept-2-en-1-yl acetate (5,7-anti-isomer) (anti-6). Prepared
according to the General Procedure 2 using alcohol anti-5 (200 mg, 0.79 mmol) and allylic
acetate S5. The product was purified by column chromatography (Pentane/Et2O = 2:1) to
furnish pure olefin anti-6 (131 mg, 41%) as a colorless oil as a 50:50 mixture of
diastereomers. Rf = 0.20 (PE/Et2O = 2:1); IR (Neat): 3436, 1731, 1602, 1493, 1454, 1371,
1234, 1018, 965 cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.36-7.19 (m, 14H), 7.15 (m, 1H), 6.15
(dd, J = 6.7 and 2.6 Hz, 1H), 5.69-5.49 (m, 2H), 4.37 (bdapp, J = 10.2 Hz, 1H), 3.07 (m, 1H),
2.44-2.32 (m, 2H), 2.09 (m, 1H), 2.07 (s, 1.5H), 2.04 (s, 1.5H), 1.90 (ddd, J = 14.3, 11.2 and
3.2 Hz, 1H), 1.85 (bs, 0.5H), 1.80 (bs, 0.5H); 13C{1H} NMR (CDCl3, 100 MHz): δ [170.2 and
170.1], [145.4 and 145.3], [144.1 and 144.0], [139.6 and 139.5], [132.7 and 132.1], [130.1
and 130.0], [128.66 (2C) and 128.65 (2C)], 128.53 (3C), 128.48, [128.1 (2C) and 128.03
(2C)], [128.00 and 127.9], [127.52 and 127.51], [127.1 (2C) and 126.8 (2C)], 126.5, 125.6
(2C), [76.2 and 76.0], [71.87 and 71.86], [45.52 and 45.50], [42.5 and 42.3], [40.28 and
40.26], [21.5 and 21.4]; LRMS (EI) m/z (rel intensity): 340 ([M-AcOH]·+, 1), 193 (24), 131
(14), 130 ([PhC4H5]·+, 13), 129 (20), 115 (30), 105 ([PhCO]+, 29), 104 ([PhC2H3]·+, 100), 103
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(18), 91 (27), 78 (18), 77 ([C6H5]+, 21); HRMS (ESI): Calculated for C27H28O3Na [M+Na]+:
423.1931, Found: 423.1929.
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(E)-7-Hydroxy-1,5,7-triphenylhept-2-en-1-yl acetate (5,7-syn-isomer) (syn-6). Prepared
according to the General Procedure 2 using alcohol syn-5 (161 mg, 0.64 mmol) and allylic
acetate S5. The product was purified by column chromatography (Pentane/EtOAc = 5:1) to
furnish pure olefin syn-6 (104 mg, 41%) as a colorless oil as a 50:50 mixture of
diastereomers. Rf = 0.29 (PE/EtOAc = 5:1); IR (Neat): 3413, 1733, 1602, 1493, 1453, 1370,
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1
1232, 1060, 1018, 964 cm-1; H NMR (CDCl3, 400 MHz): δ 7.37-7.17 (m, 13H), 7.14-7.10
(m, 2H), 6.12 (bd, J = 5.3 Hz, 1H), 5.56-5.46 (m, 2H), 4.49 (bqapp, J = 7.0 Hz, 1H), 2.54 (m,
1H), 2.43-2.27 (m, 2H), 2.19 (m, 1H), 2.09 (m, 1H), 2.06 (s, 1.5H), 2.03 (s, 1.5H), 1.78 (bd, J
= 2.7 Hz, 0.5H), 1.75 (d, J = 2.7 Hz, 0.5H); 13C{1H} NMR (CDCl3, 100 MHz): δ [170.2 and
170.1], [144.31 and 144.29], [144.24 and 144.22], [139.6 and 139.4], [132.5 and 131.7],
[130.3 and 130.2], 128.664 (3C), 128.656, [128.55 (2C) and 128.50 (2C)], [128.1 and 128.0],
[127.94 and 127.90], [127.92 (2C) and 127.88 (2C)], 127.1, 126.8, [126.533 and 126.525],
[126.46 (2C) and 126.43 (2C)], [76.2 and 75.9], [73.02 and 72.99], [44.63 and 44.57], [42.4
and 42.3], [40.00 and 39.97], [21.5 and 21.4]; LRMS (EI) m/z (rel intensity): 340 ([M-
AcOH]·+, 2), 193 (27), 131 (17), 129 (18), 115 (29), 105 ([PhCO]+, 23), 104 ([PhC2H3]·+,
100), 103 (18), 91 (20); HRMS (ESI): Calculated for C27H28O3Na [M+Na]+: 423.1931,
Found: 423.1929
(E)-5,7-Dihydroxy-1,7-diphenylhept-2-en-1-yl
acetate
(5,7-anti-isomer)
(anti-11).
Prepared according to the General Procedure 2 using alcohol anti-10 (95 mg, 0.49 mmol)
and allylic acetate S5. The product was purified by column chromatography (Pentane/EtOAc
= 3:2) to furnish pure olefin anti-11 (50 mg, 30%) as a brownish oil as a 50:50 mixture of
diastereomers. Rf = 0.24 (PE/EtOAc = 3:2); IR (Neat): 3395, 1733, 1603, 1494, 1453, 1371,
1
1235, 1058, 1022, 968 cm-1; H NMR (CDCl3, 400 MHz): δ 7.38-7.24 (m, 10H), 6.19 (m,
1H), 5.74-5.71 (m, 2H), 5.03 (bdd, J = 8.1 and 3.1Hz, 1H), 3.92 (bdapp, J = 6.1Hz, 1H), 3.25
(bs, 0.5H), 3.21 (bs, 0.5H), 2.76 (bs, 0.5H), 2.73 (bs, 0.5H), 2.29-2.25 (m, 2H), 2.08 (s, 3H),
1.94-1.79 (m, 2H); 13C{1H} NMR (CDCl3, 100 MHz): δ [170.4 and 170.3], [144.6 and
144.5], [139.4 and 139.3], [132.0 and 131.8], [130.1 and 129.8], 128.7 (2C), [128.55 (2C) and
128.53 (2C)], 128.2, [127.43 and 127.39], [127.0 (2C) and 126.9 (2C)], [125.62 (2C) and
125.60 (2C)], [76.5 and 76.2], [71.59 and 71.57], [68.2 and 68.1], [44.25 and 44.17], [40.5
and 40.4], [21.5 and 21.4]; LRMS (EI) m/z (rel intensity): 280 ([M-AcOH]·+, 1), 262 ([M-
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