Enantioselective Synthesis of Chromanones Bearing Quaternary Substituted Stereocenters Catalyzed by (1R)-Camphor-Derived N-Heterocyclic Carbenes

Article abstract of DOI:10.1021/acs.joc.5b01029

A catalytic asymmetric intramolecular crossed-benzoin reaction for the synthesis of chromanones by novel camphor-derived N-heterocyclic carbenes is described. The corresponding chromanones bearing quaternary stereogenic centers were isolated in high yield

Full text of DOI:10.1021/acs.joc.5b01029

Subscriber access provided by NEW YORK UNIV
Article
Enantioselective Synthesis of Chromanones Bearing Quaternary Substituted
Stereocentres Catalyzed by (1R)-Camphor-Derived N-Heterocyclic Carbenes
Zbigniew Rafi#ski, and Anna Kozakiewicz
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01029 • Publication Date (Web): 10 Jul 2015
Downloaded from http://pubs.acs.org on July 12, 2015
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 23
The Journal of Organic Chemistry
1
2
3
4
5
6
Enantioselective Synthesis of Chromanones Bearing Quaternary
Substituted Stereocentres Catalyzed by (1R)-Camphor-Derived N-
Heterocyclic Carbenes
7
8
9
Zbigniew Rafiński*, Anna Kozakiewicz
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
Faculty of Chemistry, Nicolaus Copernicus University in Toruń, 7 Gagarin Street, 87-100
Toruń, Poland
E-mail: payudo@chem.umk.pl
B
O
O
O
O
OH
Cl
Cl
Ar
Ar
N
N
N
O
Cl
O
up to 99% yield
up to 96% ee
* derived from cheap and commercially available camphor
* the highest enantioselective access to 3-hydroxy-4-chromanone derivatives with quaternary
stereogenic centres
Abstract: A catalytic asymmetric intramolecular crossed-benzoin reaction for the synthesis
chromanones by novel camphor-derived NHCs is described. The corresponding chromanones
bearing quaternary stereogenic centres were isolated in high yields with high to excellent
enantioselectivity.
Keywords: N-heterocyclic carbenes, camphor, benzoin, chromanones, organocatalysis
Introduction
The chromanone core is one of the characteristic structural motifs in a variety of
biologically active natural products and numerous pharmaceuticals (Figure 1).1,2
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 23
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
Figure 1. Selected natural products containing 3-hydroxy-4-chromanone core.
N-Heterocyclic carbene-catalyzed crossed benzoin reaction is a rapidly emerging area of
organocatalysis because of the unique reaction model and significant importance of the
products. For instance, Suzuki and co-workers successfully used intramolecular crossed-
aldehyde-ketone benzoin reaction in an elegant synthesis of functionalized
preanthraquinones.3 In 2006, Enders applied this reaction for the synthesis of α-hydroxy
tetralones, generating quaternary stereocenter in high enantioselectivity.4 This nice aldehyde-
ketone-based approach, proved successful in a number of interesting reactions.5 In the
context of NHC-mediated chromanone synthesis, this strategy was first explored by Suzuki in
2007 for the total synthesis of (+)-sappanone B.6 However, the competing intramolecular
aldol side reaction, induced by a base, in some cases resulted in significantly lower yield, and
hampers separation of the main product from the side products (Scheme 1).
Scheme 1. Possible Reaction Pathways
Very recently, You and co-workers devised tetracyclic triazolium salts 1, derived from (-)-
3-exo-aminoisoborneol backbone, and found them highly efficient in aldehyde-ketone
ACS Paragon Plus Environment

Page 3 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
benzoin reactions with O- and N-tethered substrates,7 Stetter-type Michael additions,8 and
desymmetrization reaction.9 However, in the case of chromanones, enantioselectivities are not
yet optimal (mostly below 90% ee) and the substrate scope is still limited. Despite the recent
advances in this field the efficient catalysts for this reaction are also limited. Therefore the
development of a novel NHC catalysts derived from natural chiral pool with improved
reactivity profiles, having fine-tuned steric and electronic environment around the carbene
centre is highly desirable. In a continuation of our ongoing efforts in the development of new
N-heterocyclic carbene catalysts, derived from monoterpenes and their applications to
organocatalytic reactions,10 we report our preliminary results on the synthesis of novel chiral
triazolium salts from (1R)-camphor and their application to the enantioselective
intramolecular crossed-benzoin reaction.
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
Results and Disscusion
Our present study began with the synthesis of various triazolium salts as outlined in
Scheme 2. (1R)-Camphor 2 was easily transformed into (‒)-3-endo-aminoborneol 3 according
to the reported method.11 The morpholinone 5 was prepared using an optimized two-step
procedure involving the formation of amide 4, followed by cyclization with potassium tert-
butoxide in excellent overall yields. A series of novel homologous triazolium salts 1a-d were
then obtained following procedures developed independently by Rovis12 and Bode.13
Additionally, their preparation does not require chromatographic purification.
Scheme 2. Synthesis of tetracyclic triazolium salts from (1R)-camphor
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 23
1
2
3
The configuration of triazolium salt 1a was confirmed by X-ray crystallographic analysis as
4
5
shown in Fig. 2.14
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
Figure 2. Crystal structure of 1a with the thermal ellipsoids plotted at 30% probability.
The potential of four new catalysts and several readily available chiral NHC precursors in the
enantioselective intramolecular crossed-benzoin reaction was tested. O-Tethered substrate 6a
reacted in the presence of NHC precatalysts 1a-d, 9a-c,10a 11a-c10b (15 mol%) and
triethylamine as a base (15 mol%) in THF for 20 h. As expected, the application of electron-
deficient triazolium derived carbenes 1c-d, 9b, 10, 11b were crucial in this type of reaction,
while other structures proved completely inactive (Table 1). When the pinene-based NHC
catalyst 9b was used, 7a was obtained in excellent 99% isolated yield (entry 2), albeit the
enantioselectivity was moderate (76:24 er). Spirocyclic NHC 11b enabled to obtain the
phenyl-substituted acryloin 7a almost quantitatively (99% yield) but with only low
enantioselectivity (60:40 er, entry 6, Table 1). To our great delight, under the same conditions,
application of novel camphor-based catalyst 1c showed excellent reactivity and very
promising asymmetric induction (98% yield of 7a, 90:10 er, entry 10). Replacing the
pentafluorophenyl group of 1c with the trichlorophenyl substituent led to α-ketol 7a with
further increase of enantiomeric excess with unchanged yield (98%, 93:7 er, entry 11, Table
1). It is worth noting that for all tested terpene-based NHC precursors, the aldol reaction
product 8 was not formed. Interestingly, the same reaction catalyzed by the aminoindanol
derived catalyst 10 afforded the desired cyclization product 7a in 90% yield, however low
enantioselectivity was observed (65:35 er, entry 4). Moreover, as in the case of previously
described Suzuki's modified aminoindanol precatalyst, the aldol product 8 was also present in
the crude products,6 and purification is difficult because of similar polarities.
ACS Paragon Plus Environment

Page 5 of 23
The Journal of Organic Chemistry
1
2
3
Table 1. Screening of Chiral NHC Catalystsa
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
Entry
NHC precat.
yield (%)b
<5
erc
1
ND
9a
2
99
76:24
ND
9b
9c
3
<5
4
90d
65:35
ND
10
5
<5
11a
11b
11c
1a
6
99
60:40
ND
7
<5
8
<5
ND
9
<5
ND
1b
1c
10
98
90:10
11
98
93:7
1d
aReaction condition: 6a (0.1 mmol), precatalyst 15 mol%, triethylamine 15 mol%, THF 1 mL
b
(0.1 M), 23 °C. Isolated yields. Determined by HPLC analysis using a chiral stationary
c
phase. dThe corresponding aldol product was observed.
Next, we focused our attention on additional optimization to improve reaction
enantioselectivity was carried using various bases and solvents (Table 2). In this regard, all
the tested organic bases were tolerable and gave the desired α-ketol 7a in high
enantioselectivity and excellent yields. In the presence of 1,4-diazabicyclo[2.2.2]octane
(DABCO) or 4-(dimethylamino)pyridine (DMAP), the reaction proceed smoothly, albeit a
slight erosion of the er value was observed (entries 6-7, Table 2). Surprisingly, when the
phosphazene base BEMP was used, the reaction went also smoothly to give the desired 3-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 23
1
2
3
4
5
6
7
8
9
hydroxychromanone 7a in almost quantitative yield and excellent enantioselectivity within 30
minutes (98% yield, 92% ee, entry 11, Table 2). Among the various solvent screened, the
reaction in TAME, o-xylene and MTBE resulted in comparable results (entry 13-15), whereas
the reaction in polar protic and aprotic solvents such as ethanol, DMF and octafluorotoluene,
the desired product was not obtained. Finally, cyclopentyl methyl ether was found to be the
optimal solvent, and 7a was obtained in less than 1 h in 99% yield, with a slightly improved
er (96.5:3.5).
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. Reaction Optimizationa
entry
1
solvent
THF
base
time (h)
20
yield (%)b
98
erc
NEt3
93:7
2
THF
DIPEA
DCyEA
Pempidine
DBU
20
99
93:7
3
THF
20
98
94:6
4
THF
20
98
90:10
94:6
5
THF
20
93
6
THF
DABCO
DMAP
KHMDS
P2-Et
20
90
89:11
86:14
92:8
7
THF
20
91
8
THF
20
92
9
THF
20
98
92:8
10
11
12
13
14
15
16
THF
P2-tBu
BEMP
BEMP
BEMP
BEMP
BEMP
BEMP
20
98
92:8
THF
0.5
18
99
96:4
CH2Cl2
MTBE
TAME
o-xylene
CPME
99
92.5:7.5
95:5
2
97
2
99
95:5
0.5
0.75
99
94:6
99
96.5:3.5
ACS Paragon Plus Environment

Page 7 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
17
18
19
DMF
OFT
BEMP
BEMP
BEMP
48
48
48
<5
ND
NR
NR
------
------
EtOH
aReaction condition: 6a (0.1 mmol), precatalyst 15 mol%, base 15 mol% in 0.1 M in solvent
b
(1 mL), and at rt. Isolated yields. Determined by HPLC analysis using a chiral stationary
c
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
phase. BEMP: 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diaza-
phosphorine, OFT: octafluorotoluene; DCyEA: dicyclohexylethylamine; CMPE: cyclopentyl
methyl ether; TAME: tert-amyl methyl ether.
Encouraged by these results, the scope of the reaction was explored using a series of aryl
substituted O-tethered substrates. The results are shown in Scheme 3. The reaction performed
with both electron-withdrawing (4-BrC6H5-7b, 4-FC6H5-7c and 4-CF3OC6H5-7d) and
electron-donating substituents (7f) on the phenyl group could be well tolerated, afforded the
cross-benzoin products in high yields and enantiomeric excess. However, due to the lower
reactivity in the case of electron-withdrawing groups (7b, 7c and 7i) we used modified
protocol by replacing BEMP with diisopropylethylamine, but the desired products are still
obtained with high stereocontrol. Cyclization of 2,4-disubstituted aryl ketone (7h) occurred
also efficiency with high yield, however a slightly lower enantioselectivity was observed.
Replacing the phenyl group with naphtyl gave the desired chromanone 7e with excellent yield
and very high enantioselectivity (97% yield, 95% ee). The use of a large 4-phenyl aryl ketone
also worked well, affording the desired product 7j with high stereocontrol (98:2 er).
Unfortunately, when the aryl group was replaced with small methyl, cyclization product 7k
was afforded with decreased selectivity (72:28 er) although the yield remained excellent (99%
yield within 20 min.)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 23
1
2
3
Scheme 3. Scope of the Cross-Benzoin Reactiona
4
5
6
7
O
O
O
R2
OH
1d
15 mol% NHC
R1
R1
R2
BEMP 15 mol%
CPME (0.1M), rt, 1h
O
8
9
O
7a-j
6a-j
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
7k, Me
Ar
instead of
6k, Me
Ar
instead of
O
O
O
OH
OH
OH
F
Br
O
O
O
b
b
7a
7b
7c
: 99% yield
96.5:3.5 er
: 91% yield
: 81% yield
96:4 er
97:3 er
O
O
O
OH
OH
OH
OCF3
OMe
O
O
O
7d
: 91% yield
95:5 er
7e
: 99% yield
97.5:2.5 er
7f
: 98% yield
97:3 er
O
O
OMe
O
OH
OH
OH
Me
OMe
F
O
O
O
F
b
7i
: 82% yield
7g
: 98% yield
93:7 er
7h: 97% yield
91:9 er
95:5 er
O
O
O
OH
OH
Me
O
7j
: 98% yield
98:2 er
7k
: 99% yield
72:28 er
aUnless otherwise noted, all reactions were performed with keto-aldehyde substrate (0.2
mmol), NHC precatalyst 1d 15 mol%, BEMP 15 mol% in CPME (2 mL) at rt for 1 h. Yields
of isolated product after column chromatography. The er values were determined by HPLC
analysis using a chiral stationary phase.b For electron-withdrawing substituents DIPEA (100
mol%) instead BEMP was used. The reaction proceeded for 20 h.
We have carried out additional experiments to show the usefulness of triazolium salts 1b,d in
the Stetter reaction and aza-diene Diels-Alder reaction.15 Cyclization of salicylaldehyde-
ACS Paragon Plus Environment

Page 9 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
derived substrate 12 occurred very efficiency to give the chromanone 13 in a excellent yield
with 95% ee. The reaction of enal and an α,β-unsaturated imine catalyzed by NHC-1b,
proceeded smoothly to afford dihydropiridinone 14 with high yield and excellent
enantioselectivity (Scheme 4).
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
Scheme 4. Application of NHC Precursors 1b,d in Other Reactions
Conclusion
In summary, a series of novel chiral NHC precursors derived from readily available (1R)-
camphor for enantioselective cross-benzoin reaction with O-tethered substrates was
developed. Various substituted 3-hydroxy-3-aryl-4-chromanone derivatives having a
quaternary stereogenic centre were obtained with high to excellent yield and stereocontrol.
Moreover, the excellent reactivity of substrates with electron-donating substituent on the
phenyl group is noteworthy, since all reactions were completed within 1 h. Notable, the
generally better enantioselectivities for the chromanone-derived products facilitated by our
catalytic system were observed. Further application of the methodology in organic synthesis,
and development of new enantioselective catalytic reactions using these camphor-derived
triazolium salts are currently underway.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 23
1
2
Experimental section
3
4
5
6
7
8
General information: Reactions involving moisture sensitive reagents were carried out under
a nitrogen atmosphere using standard vacuum line techniques. All glassware used was flame
dried and cooled under vacuum. Anhydrous diethyl ether, tert-butyl methyl ether, cyclopentyl
methyl ether, tert-amyl methyl ether, THF, DME, toluene, o-xylene and were distilled from
sodium and benzophenone Anhydrous dichloromethane was obtained by distillation over
calcium hydride. All other solvents and commercial reagents were used as supplied without
further purification unless stated otherwise. Analytical thin layer chromatography was
performed on pre-coated aluminium plates (Kieselgel 60 F254silica). TLC visualisation was
carried out with ultraviolet light (254 nm), followed by staining with a 1% aqueous KMnO4
solution. Column chromatography was performed with silica gel 70-230 mesh.
NMR spectra were recorded on either 700 (1H, 700 MHz; 13C, 176 MHz) or 400 (1H, 400
MHz; 13C, 100 MHz), using CDCl3 as solvent, and were reported in ppm relative to CHCl3 (δ
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
1
7.26) for H NMR and relative to the central CDCl3 (δ 77.00) resonance for 13C NMR.
1
Coupling constants (J) in H NMR are in Hz. Multiplicities are indicated by: s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), ddd (doublet of
doublet of doublets), dt (doublet of triplets), td (triplet of doublets)and dtd (doublet of triplets
of doublets). Melting points were obtained in open capillary tubes using a micro melting point
apparatus and were uncorrected. Optical rotations were measured using a 1.0 mL cell with a
0.1 dm path length. Low-resolution mass spectra (LRMS) were recorded using the ESI mode
(TOF). All other reagents were purchased from commercial suppliers. Catalyst 1a-d were
prepared according to the known methods.10a-b,12-13 Starting materials 4, 5 were prepared
according to the known method.10a For 1c, in the 13C NMR fluorine couplings are not
included due to the complexity of the perfluoro couplings.
2-Chloro-N-((1S,2S,3R,4R)-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]heptan-2-
21
1
yl)acetamide (4). White solid, 96% yield. M.p. 57-60 °C. [α]D = +4.9 (c 2.0, CHCl3). H
NMR (700 MHz, CDCl3) δ: 0.89 (s, 3H), 0.94 (s, 3H), 0.96 (s, 3H), 1.21 (dtd, J = 12.8, 4.4,
2.0 Hz, 1H), 1.37 (dddd, J = 22.8, 13.6, 9.6, 4.4 Hz, 1H), 1.47-1.56 (m, 1H), 1.85 (dddd, J =
22.4, 14.0, 9.6, 4.8 Hz, 1H), 2.06 (t, J = 4.0 Hz, 1H), 2.32 (d, J = 4.8 Hz, 1H), 4.03 (ddd, J =
9.6, 4.8, 2.0 Hz, 1H), 4.08 (s, 2H), 4.19-4.24 (m, 1H), 7.35 (bs, 1H). 13C NMR (100 MHz,
CDCl3) δ: 13.8, 18.3, 19.6, 19.9, 25.3, 42.8, 45.4, 48.5, 49.7, 49.8, 73.5, 166.0. LRMS (ESI):
Mass calcd for [M+Na+MeOH]+ C13H24ClNO3Na: 300.1; found 300.4. Anal. calcd for
C12H20ClNO2: C, 58.65; H, 8.20; Found: C, 58.77; H, 8.30.
ACS Paragon Plus Environment

Page 11 of 23
The Journal of Organic Chemistry
1
2
(4aS,5S,8R,8aR)-8,9,9-Trimethylhexahydro-2H-5,8-methanobenzo[b][1,4]oxazin-
3
4
5
6
7
8
9
21
1
3(4H)-one (5). White solid, 95% yield. M.p. 179-181 °C. [α]D = −6.5 (c 2.1, CHCl3). H
NMR (700 MHz, CDCl3) δ: 0.96 (s, 3H), 0.98 (s, 3H), 0.99 (s, 3H), 1.29 (dtd, J = 12.6, 4.9,
1.4 Hz, 1H), 1.53-1.58 (m, 1H), 1.64-1.78 (m, 1H), 1.83 (t, J = 4.9 Hz, 1H), 2.01 (dddd, J =
22.4, 13.3, 9.8, 4.2 Hz, 1H), 3.82 (dd, J = 9.1, 4.9 Hz, 1H), 3.86 (d, J = 9.1 Hz, 1H), 3.90 (d, J
= 15.4 Hz, 1H), 4.20 (d, J = 15.4 Hz, 1H), 5.76 (bs, 1H). 13C NMR (176 MHz, CDCl3) δ: 13.8,
18.6, 18.9, 20.0, 26.6, 46.8, 49.0, 49.6, 51.0, 66.6, 78.7, 173.2. LRMS (ESI): Mass calcd for
[2M+Na]+ C24H38N2O4Na: 441.3; found 441.5. Anal. calcd for C12H19NO2: C, 68.87; H, 9.15;
Found: C, 68.95; H, 9.22.
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
(5aR,6R,9S,9aS)-6,11,11-Trimethyl-2-phenyl-5a,6,7,8,9,9a-hexahydro-4H-6,9-
methanobenzo-[b][1,2,4]triazolo[4,3-d][1,4]oxazin-2-ium tetrafluoroborate (1a). White
solid, 74% yield. M.p. 274-277 °C. [α]D21 = +5.2 (c 1.3, CHCl3). 1H NMR (700 MHz, CDCl3)
δ: 0.88-0.93 (m, 1H), 0.95 (s, 3H), 0.97 (s, 3H), 1.00 (s, 3H), 1.29-1.33 (m, 1H), 1.65-1.71 (m,
1H), 1.83 (dddd, J = 22.4, 13.3, 9.1, 4.2 Hz, 1H), 2.70 (t, J = 4.2 Hz, 1H), 4.23 (d, J = 9.1 Hz,
1H), 4.82 (d, J = 15.4 Hz, 1H), 4.87 (dd, J = 4.2, 9.1 Hz, 1H), 5.10 (d, J = 15.4 Hz, 1H), 7.46-
7.53 (m, 3H), 7.84-7.87 (m, 2H), 10.08 (s, 1H). 13C NMR (176 MHz, CDCl3) δ: 14.5, 19.3,
20.4, 20.5, 27.4, 48.2, 48.7, 51.1, 56.6, 60.6, 80.1, 121.6 (2C), 131.2 (2C), 131.7, 135.9,
140.2, 154.0. LRMS (ESI): Mass calcd for [M]+ C19H24N3O: 310.4; found 310.4. Anal. calcd
for C19H24BF4N3O: C, 57.45; H, 6.09; Found: C, 57.40; H, 6.07.
(5aR,6R,9S,9aS)-2-Mesityl-6,11,11-trimethyl-5a,6,7,8,9,9a-hexahydro-4H-6,9-
methanobenzo-[b][1,2,4]triazolo[4,3-d][1,4]oxazin-2-ium chloride (1b). White solid, 75%
yield. M.p. = 307-310 °C. [α]D = +7.3 (c 1.0, CHCl3). 1H NMR (700 MHz, CDCl3) δ: 0.85
21
(dddd, J = 23.1, 14.0, 9.1, 4.9 Hz, 1H), 1.03 (s, 3H), 1.04 (s, 3H), 1.11 (s, 3H), 1.37 (dt, J =
11.9, 4.9 Hz, 1H), 1.73-1.79 (m, 1H), 1.87 (dddd, J = 22.4, 12.6, 9.1, 4.9 Hz, 1H), 2.14 (s,
6H), 2.35 (s, 3H), 3.12 (m, 1H), 4.25 (d, J = 8.4 Hz, 1H), 4.69 (d, J = 14.7 Hz, 1H), 5.14-5.17
(m, 2H), 7.01 (s, 2H), 11.67 (s, 1H). 13C NMR (176 MHz, CDCl3) δ: 14.5, 18.7, 19.6, 20.4
(2C), 20.5, 22.2, 27.5, 48.2, 49.6, 51.4, 56.8, 60.6, 80.4, 130.8 (2C), 132.1, 135.8, 143.0 (2C),
146.3, 153.0. LRMS (ESI): Mass calcd for [M]+ C22H30N3O: 352.2; found 352.3. Anal. calcd
for C22H30ClN3O: C, 68.11; H, 7.79; Found: C, 68.20; H, 7.85.
(5aR,6R,9S,9aS)-6,11,11-Trimethyl-2-(perfluorophenyl)-5a,6,7,8,9,9a-hexahydro-4H-
6,9-methanobenzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-2-ium tetrafluoroborate (1c). Pale
yellow solid, 68% yield. M.p. 110-114 °C. [α]D21 = +1.8 (c 1.0, CHCl3). H NMR (700 MHz,
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 23
1
2
3
4
5
6
7
8
9
CDCl3) δ: 0.85 (dddd, J = 23.1, 14.0, 9.8, 5.6 Hz, 1H), 1.03 (s, 3H), 1.04 (s, 3H), 1.06 (s, 3H),
1.36 (dt, J = 11.9, 4.9 Hz, 1H), 1.71-1.77 (m, 1H), 1.86 (dddd, J = 23.1, 14.0, 9.8, 4.2 Hz,
1H), 2.52 (t, J = 4.2 Hz, 1H), 4.28 (d, J = 9.1 Hz, 1H), 4.85 (d, J = 15.4 Hz, 1H), 4.93 (dd, J =
7.0, 4.2 Hz, 1H), 5.09 (d, J = 15.4 Hz, 1H), 9.97 (s, 1H). 13C NMR (176 MHz, CDCl3) δ: 14.4,
19.3, 20.4, 20.5, 27.3, 48.3, 48.8, 51.0, 56.9, 60.4, 79.9, 111.8, 138.3, 138.8, 139.7, 143.6,
145.0, 146.6, 154.9. LRMS (ESI): Mass calcd for [M]+ C19H19F5N3O: 400.4; found 400.4.
Anal. calcd for C19H19BF9N3O: C, 46.84; H, 3.93; Found: C, 46.89; H, 3.99.
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
(5aR,6R,9S,9aS)-6,11,11-Trimethyl-2-(2,4,6-trichlorophenyl)-5a,6,7,8,9,9a-hexahydro-
4H-6,9-methanobenzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-2-ium tetraphenylborate (1d).
21
1
White solid, 46% yield. M.p. 145-147 °C. [α]D = −5.4 (c 1.2, CHCl3). H NMR (700 MHz,
CDCl3) δ: 0.41 (dddd, J = 23.1, 14.0, 9.1, 4.8 Hz, 1H), 0.93 (s, 3H), 0.96 (s, 3H), 1.04 (s, 3H),
1.20-1.27 (m, 1H), 1.53-1.62 (m, 2H), 2.33 (t, J = 4.8 Hz, 1H), 2.45 (dd, J = 9.1, 4.8 Hz, 1H),
3.74 (d, J = 9.1 Hz, 1H), 4.46 (d, J = 15.4 Hz, 1H), 5.00 (d, J = 15.4 Hz, 1H), 5.66 (s, 1H),
6.68-6.93 (m, 12H), 7.36-7.42 (m, 8H), 7.65 (s, 1H), 7.70 (s, 1H). 13C NMR (176 MHz,
CDCl3) δ: 13.3, 18.7, 19.1, 19.6, 25.8, 47.1, 47.8, 50.0, 54.5, 59.1, 79.2, 122.2 (4C), 125.7
(8C), 129.0, 129.4, 130.2, 133.9, 134.7, 136.3 (8C), 139.8, 144.8, 152.3, 163.1, 163.6, 164.1,
164.6. LRMS (ESI): Mass calcd for [M]+ C19H21Cl3N3O: 412.1; found 412.4. Anal. calcd for
C43H41BCl3N3O: C, 70.46; H, 5.64; Found: C, 70.55; H, 5.53.
General procedure for the preparation of keto-aldehyde 6a-j
Step I: To a solution of the dithiane16 (9.4 mmol) in dimethylformamide (9.5 mL) was added
K2CO3 (1.5 g, 10.8 mmol). After stirring for 0.5 h, ω-bromoacetophenone derivative (9.4
mmol) was added and the mixture was stirred at room temperature overnight. After
completion (monitored by TLC), water was added to the solution, and the mixture was
extracted with ethyl acetate. The combined ethyl acetate extract was washed with brine, dried
over anhydrous MgSO4 and then concentrated under reduced pressure. The crude product was
purified by column chromatography (Petroleum ether/EtOAc, 8:2).
ACS Paragon Plus Environment

Page 13 of 23
The Journal of Organic Chemistry
1
2
3
2-(2-(1,3-Dithian-2-yl)phenoxy)-1-phenylethanone (15a). Yellow solid, 92% yield (2.86
4
5
1
g). M.p. = 95-98 °C. H NMR (400 MHz, CDCl3) δ: 1.89-2.00 (m, 1H), 2.13-2.20 (m, 1H),
6
7
8
9
2.87-2.92 (m, 2H), 3.03-3.11 (m, 2H), 5.31 (s, 2H), 5.79 (s, 1H), 6.84 (dd, J = 8.0, 0.8 Hz,
1H), 7.03 (dt, J = 7.6, 0.8 Hz, 1H), 7.25 (dddd, J = 15.6, 8.4, 7.6, 1.6 Hz, 1H), 7.50-7.55 (m,
2H), 7.62-7.66 (m, 2H), 8.02-8.06 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 25.3, 32.4 (2C),
44.0, 72.0, 112.7, 122.3, 128.3 (2C), 128.4, 128.8 (2C), 129.4, 129.5, 133.8, 134.7, 154.2,
194.4. LRMS (ESI): Mass calcd for [M+Na]+ C18H18S2O2Na: 353.1; found 353.3. Anal. calcd
for C18H18S2O2: C, 65.42; H, 5.49; Found: C, 65.31; H, 5.38.
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-(1,3-Dithian-2-yl)phenoxy)-1-(4-bromophenyl)ethanone (15b). Ochre solid, 98%
1
yield (3.77 g). M.p. = 107-109 °C. H NMR (700 MHz, CDCl3) δ: 1.92-1.99 (m, 1H), 2.15-
2.21 (m, 1H), 2.90-2.93 (m, 2H), 3.02-3.08 (m, 2H), 5.24 (s, 2H), 5.73 (s, 1H), 6.84 (d, J =
7.7 Hz, 1H), 7.06 (t, J = 7.0 Hz, 1H), 7.25-7.28 (m, 1H), 7.64 (dd, J = 7.7, 1.4 Hz, 1H), 7.66-
13
7.69 (m, 2H), 7.90-7.94 (m, 2H). C NMR (100 MHz, CDCl3) δ: 25.3, 32.4 (2C), 44.0, 72.0,
112.5, 122.4, 128.3, 129.0, 129.4, 129.5, 130.0 (2C), 132.1 (2C), 133.4, 154.0, 193.8. LRMS
(ESI): Mass calcd for [M+Na]+ C18H17BrS2O2Na: 431.0; found 431.1. Anal. calcd for
C18H17BrS2O2: C, 52.81; H, 4.19; Found: C, 52.71; H, 4.12.
2-(2-(1,3-Dithian-2-yl)phenoxy)-1-(4-fluorophenyl)ethanone (15c). Yellow solid, 99%
1
yield (3.24 g). M.p. = 153-155 °C. H NMR (700 MHz, CDCl3) δ: 1.92-1.99 (m, 1H), 2.16-
2.20 (m, 1H), 2.90-2.93 (m, 2H), 3.04-3.09 (m, 2H), 5.26 (s, 2H), 5.76 (s, 1H), 6.83 (d, J =
9.1 Hz, 1H), 7.05 (t, J = 7.0 Hz, 1H), 7.18-7.21 (m, 2H), 7.25-7.28 (m, 1H), 7.65 (dd, J = 7.7,
13
1.4 Hz, 1H), 8.09-8.12 (m, 2H). C NMR (100 MHz, CDCl3) δ: 25.3, 32.4 (2C), 44.0, 72.0,
112.5, 115.9, 116.1, 122.4, 128.3, 129.4 (d, J = 4.7 Hz, 2C), 131.1 (d, J = 3.1 Hz), 131.2 (d, J
= 9.5 Hz, 2C), 154.0, 165.0 (d, J = 254.4 Hz), 193.0. LRMS (ESI): Mass calcd for [M+Na]+
C18H17FS2O2Na: 371.1; found 371.1. Anal. calcd for C18H17FS2O2: C, 62.04; H, 4.92; Found:
C, 61.93; H, 4.85.
2-(2-(1,3-Dithian-2-yl)phenoxy)-1-(4-(trifluoromethoxy)phenyl)ethanone
(15d).
1
Yellow oil, 75% yield (2.92 g). H NMR (700 MHz, CDCl3) δ: 1.92-1.98 (m, 1H), 2.16-2.19
(m, 1H), 2.89-2.93 (m, 2H), 3.02-3.06 (m, 2H), 5.26 (s, 2H), 5.73 (s, 1H), 6.85 (dd, J = 1.4,
8.4 Hz, 1H), 7.07 (dt, J = 7.7, 0.7 Hz, 1H), 7.27 (ddd, J = 16.1, 7.7, 1.4 Hz, 1H), 7.34-7.37
(m, 2H), 7.65 (dd, J = 7.7, 1.4 Hz, 1H), 8.13-8.15 (m, 2H). 13C NMR (100 MHz, CDCl3) δ:
25.3, 32.3 (2C), 44.0, 72.0, 112.4, 120.0 (q, J = 257.5 Hz), 120.5, 122.5, 128.3, 129.5, 129.6
(2C), 130.7 (2C), 132.9, 153.0, 153.9, 193.3. LRMS (ESI): Mass calcd for [M+Na]+
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 23
1
2
3
4
5
C19H17F3S2O3Na: 437.0; found 437.3. Anal. calcd for C19H17F3S2O3: C, 55.06; H, 4.13;
Found: C, 55.18; H, 4.16.
6
7
2-(2-(1,3-Dithian-2-yl)phenoxy)-1-(naphthalen-2-yl)ethanone (15e). Yellow solid, 87%
8
9
1
yield (3.11 g). M.p. = 154-157 °C. H NMR (700 MHz, CDCl3) δ: 1.86-1.92 (m, 1H), 2.05-
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
2.10 (m, 1H), 2.80-2.84 (m, 2H), 2.91-2.96 (m, 2H), 5.39 (s, 2H), 5.77 (s, 1H), 6.89 (dd, J =
7.7, 0.7 Hz, 1H), 7.03 (dt, J = 7.0, 0.7 Hz, 1H), 7.24-7.27 (m, 1H), 7.55-7.58 (m, 1H), 7.62-
7.64 (m, 2H), 7.90 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 8.07
(dd, J = 8.4, 1.4 Hz, 1H), 8.60 (d, J = 0.7 Hz, 1H). 13C NMR (176 MHz, CDCl3) δ: 24.9, 32.0
(2C), 43.6, 71.8, 112.1, 122.0, 123.4, 126.5, 127.5, 127.9, 128.3, 128.5, 129.0, 129.1, 129.4,
130.1, 131.6, 132.0, 135.5, 153.7, 194.1. LRMS (ESI): Mass calcd for [M+Na]+
C22H20S2O2Na: 380.1; found 380.2. Anal. calcd for C22H20S2O2: C, 69.44; H, 5.30; Found: C,
69.35; H, 5.21.
2-(2-(1,3-Dithian-2-yl)phenoxy)-1-(4-methoxyphenyl)ethanone (15f). Yellow solid,
96% yield (3.25 g). M.p. = 89-90 °C. 1H NMR (700 MHz, CDCl3) δ: 1.93-2.00 (m, 1H), 2.17-
2.21 (m, 1H), 2.90-2.93 (m, 2H), 3.08-3.12 (m, 2H), 3.92 (s, 3H, OCH3), 5.27 (s, 2H), 5.80 (s,
1H), 6.84 (dd, J = 8.4, 1.4 Hz, 1H), 6.99-7.01 (m, 2H), 7.04 (dt, J = 7.7, 1.4 Hz, 1H), 7.25
(dddd, J = 15.4, 9.1, 7.7, 1.4 Hz, 1H), 7.64 (dd, J = 7.7, 1.4 Hz, 1H), 8.05-8.07 (m, 2H). 13C
NMR (100 MHz, CDCl3) δ: 25.3, 32.4 (2C), 44.0, 55.6, 71.8, 112.6, 114.0 (2C), 122.2, 127.7,
128.3, 129.3, 129.4, 130.7 (2C), 154.2, 164.0, 192.8. LRMS (ESI): Mass calcd for [M+Na]+
C19H20S2O3Na: 383.1; found 383.2. Anal. calcd for C19H20S2O3: C, 63.30; H, 5.59; Found: C,
63.35; H, 5.48.
2-(2-(1,3-Dithian-2-yl)-4-methylphenoxy)-1-phenylethanone (15g). Brown solid, 88%
1
yield (2.85 g). M.p. = 108-111 °C. H NMR (700 MHz, CDCl3) δ: 1.89-2.00 (m, 1H), 2.13-
2.20 (m, 1H), 2.28 (s, 3H), 2.86-2.90 (m, 2H), 3.02-3.07 (m, 2H), 5.26 (s, 2H), 5.74 (s, 1H),
6.73 (d, J = 8.4 Hz, 1H), 7.02 (m, 1H), 7.41 (d, J = 2.1 Hz, 1H), 7.48-7.51 (m, 2H), 7.60-7.63
(m, 1H), 8.00-8.05 (m, 2H). 13C NMR (176 MHz, CDCl3) δ: 21.5, 26.4, 33.4 (2C), 45.1, 73.3,
113.9, 129.1, 129.3 (2C), 129.8 (2C), 130.8, 130.9, 132.8, 134.7, 135.8, 153.1, 195.6. LRMS
(ESI): Mass calcd for [M+Na]+ C19H20S2O2Na: 367.1; found 367.1. Anal. calcd for
C19H20S2O2: C, 66.24; H, 5.85; Found: C, 66.30; H, 5.92.
2-(2-(1,3-Dithian-2-yl)phenoxy)-1-(2,4-dimethoxyphenyl)ethanone (15h). Pink solid,
1
87% yield (3.19 g). M.p. = 138-140 °C. H NMR (700 MHz, CDCl3) δ: 1.93-1.99 (m, 1H),
2.16-2.20 (m, 1H), 2.90-2.93 (m, 2H), 3.09-3.14 (m, 2H), 3.91 (s, 3H; OCH3), 3.93 (s, 3H;
ACS Paragon Plus Environment

Page 15 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
OCH3), 5.26 (s, 2H), 5.83 (s, 1H), 6.14 (d, J = 2.1 Hz, 1H), 6.63 (dd, J = 8.4, 2.1 Hz, 1H),
6.75 (dd, J = 8.4, 0.7 Hz, 1H), 7.00 (dt, J = 8.4, 1.4 Hz, 1H), 7.22 (ddd, J = 9.1, 7.0, 1.4 Hz,
1H), 7.63 (dd, J = 7.7, 2.1 Hz, 1H), 8.01 (d, J = 9.1 Hz, 1H). 13C NMR (176 MHz, CDCl3) δ:
26.4, 33.4 (2C), 44.1, 56.6, 56.7, 76.0, 99.1, 106.8, 113.5, 119.3, 122.6, 129.0, 130.2 (2C),
134.1, 155.7, 162.2, 166.2, 194.4. LRMS (ESI): Mass calcd for [M+Na]+ C20H22S2O4Na:
413.1; found 413.2. Anal. calcd for C20H22S2O4: C, 61.51; H, 5.68; Found: C, 61.58; H, 5.76.
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-(1,3-Dithian-2-yl)phenoxy)-1-(3,4-difluorophenyl)ethanone (15i). Yellow solid,
82% yield (2.82 g). M.p. = 76-79 °C. 1H NMR (700 MHz, CDCl3) δ: 1.93-2.00 (m, 1H), 2.18-
2.22 (m, 1H), 2.92-2.95 (m, 2H), 3.05-3.10 (m, 2H), 5.23 (s, 2H), 5.74 (s, 1H), 6.84 (dd, J =
7.7, 0.7 Hz, 1H), 7.07 (dd, J = 7.7, 1.4 Hz, 1H), 7.27 (m, 1H), 7.30-7.34 (m, 1H), 7.65 (dd, J =
7.7, 1.4 Hz, 1H), 7.86-7.90 (m, 1H), 7.95 (dddd, J = 18.2, 10.5, 7.7, 2.1 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ: 25.3, 32.4 (2C), 44.0, 72.0, 112.4, 117.8 (d, J = 18.2 Hz), 118.0 (d, J =
18.2 Hz), 122.6, 125.8 (dd, J = 7.9, 4.0 Hz) 128.3, 129.5, 129.6, 131.7 (t, J = 4.0 Hz), 150.5
(dd, J = 249.6, 12.6 Hz), 153.8, 154.0 (dd, J = 256.7, 12.6 Hz), 192.4. LRMS (ESI): Mass
calcd for [M+Na]+ C18H16F2S2O2Na: 389.0; found 389.3. Anal. calcd for C18H16F2S2O2: C,
59.00; H, 4.40; Found: C, 59.13; H, 4.47.
2-(2-(1,3-Dithian-2-yl)phenoxy)-1-([1,1'-biphenyl]-4-yl)ethanone (15j). Light orange
1
solid, 89% yield (3.40 g). M.p. = 112-114 °C. H NMR (700 MHz, CDCl3) δ: 1.92-1.99 (m,
1H), 2.16-2.20 (m, 1H), 2.90-2.93 (m, 2H), 3.07-3.11 (m, 2H), 5.35 (s, 2H), 5.82 (s, 1H), 6.88
(dd, J = 8.4, 1.4 Hz, 1H), 7.07 (dt, J = 7.0, 0.7 Hz, 1H), 7.28 (dddd, J = 15.4, 8.4, 7.7, 1.4 Hz,
1H), 7.44-7.46 (m, 1H), 7.50-7.53 (m, 2H), 7.65-7.68 (m, 3H), 7.74-7.77 (m, 2H), 8.12-8.15
(m, 2H). 13C NMR (100 MHz, CDCl3) δ: 25.4, 32.4 (2C), 44.1, 72.1, 112.7, 122.4, 127.3
(2C), 127.4 (2C), 128.3, 128.5, 129.0 (2C), 129.1 (2C), 129.4, 129.5, 133.4, 139.7, 146.4,
154.2, 194.0. LRMS (ESI): Mass calcd for [M+Na]+ C24H22S2O2Na: 429.1; found 429.2.
Anal. calcd for C24H22S2O2: C, 70.90; H, 5.45; Found: C, 70.93; H, 5.48.
Step II. To a solution of keto-dithane (7.0 mmol) in dichloromethane (82 mL) and methanol
(1.2 mL) was added mercury trifluoroacetate (4.9 g, 10.5 mmol, 1.5 equiv) and the resulting
cloudy solution was stirred until reaction was judged to be complete by TLC. The reaction
mixture was then filtered through Celite pad and the resulting solution was concentrated in
vacuo. The desired product was purified by crystallization with a solution of petroleum ether
and ethyl acetate.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 23
1
2
3
4
5
6
7
8
9
1
2-(2-Oxo-2-phenylethoxy)benzaldehyde (6a). Ochre solid, 88% yield (1.48 g). H NMR
(400 MHz, CDCl3) δ: 5.45 (s, 2H), 6.89 (d, J = 8.0 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 7.50-
7.56 (m, 3H), 7.64-7.69 (m, 1H), 7.89 (dd, J = 7.6, 1.6 Hz, 1H), 8.00-8.03 (m, 2H), 10.61 (s,
1H). 13C NMR (100 MHz, CDCl3) δ: 70.9, 112.8, 121.7, 125.4, 128.0 (2C), 128.7, 129.0 (2C),
134.2, 134.3, 135.7, 160.3, 189.6, 193.6. LRMS (ESI): Mass calcd for [M+Na]+ C15H12O3Na:
263.1; found 263.1. Anal. calcd for C15H12O3: C, 74.99; H, 5.03; Found: C, 75.06; H, 5.09.
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-(4-Bromophenyl)-2-oxoethoxy)benzaldehyde (6b). Beige solid, 99% yield (2.21 g).
1
M.p. = 155-158 °C. H NMR (700 MHz, CDCl3) δ: 5.40 (s, 2H), 6.90 (d, J = 7.7 Hz, 1H),
7.10-7.13 (m, 1H), 7.55 (dddd, J = 16.1, 8.4, 7.0, 2.1 Hz, 1H), 7.68-7.72 (m, 2H), 7.89-7.92
(m, 3H), 10.59 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 71.9, 113.7, 122.9, 126.4, 129.9,
130.5, 130.6 (2C), 133.4 (2C), 133.9, 136.8, 161.1, 190.4, 198.8. LRMS (ESI): Mass calcd for
[M+Na]+ C15H11BrO3Na: 343.2; found 343.2. Anal. calcd for C15H11BrO3: C, 56.45; H, 3.47;
Found: C, 56.56; H, 3.52.
2-(2-(4-Fluorophenyl)-2-oxoethoxy)benzaldehyde (6c). Yellowish solid, 99% yield (1.79
1
g). M.p. = 121-122 °C. H NMR (700 MHz, CDCl3) δ: 5.41 (s, 2H), 6.90 (d, J = 7.7 Hz, 1H),
7.11-7.13 (m, 1H), 7.21-7.24 (m, 2H), 7.55 (dddd, J = 16.1, 8.4, 7.7, 2.1 Hz, 1H), 7.91 (dd, J
= 7.7, 2.1 Hz, 1H), 8.06-8.09 (m, 2H), 10.60 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 70.8,
112.8, 116.2 (d, J = 22.1 Hz, 2C), 121.8, 125.3, 128.7, 130.6 (d, J = 3.2 Hz), 130.8 (d, J = 9.5
Hz, 2C), 135.8, 160.2, 161.1 (d, J = 255.2 Hz), 189.5, 192.1. LRMS (ESI): Mass calcd for
[M+Na]+ C15H11FO3Na: 281.1; found 281.2. Anal. calcd for C15H11FO3: C, 69.76; H, 4.29;
Found: C, 69.82; H, 4.40.
2-(2-Oxo-2-(4-(trifluoromethoxy)phenyl)ethoxy)benzaldehyde (6d). White solid, 89%
1
yield (2.02 g). M.p. = 143-145 °C. H NMR (700 MHz, CDCl3) δ: 5.40 (s, 2H), 6.90 (d, J =
8.4 Hz, 1H), 7.13 (t, J = 7.0 Hz, 1H), 7.38 (d, J = 8.4, 2H), 7.53-7.56 (m, 1H), 7.92 (dd, J =
7.7, 1.4 Hz, 1H), 8.09-8.12 (m, 2H), 10.60 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 70.9,
112.7, 120.3 (q, J = 258.0 Hz), 120.7 (2C), 121.9, 125.4, 128.9, 130.3 (2C), 132.4, 135.8,
153.3, 160.1, 189.4, 192.2. LRMS (ESI): Mass calcd for [M+Na]+ C16H11F3O4Na: 347.1;
found 347.3. Anal. calcd for C16H11F3O4: C, 59.27; H, 3.42; Found: C, 59.40; H, 3.49.
2-(2-(Naphthalen-2-yl)-2-oxoethoxy)benzaldehyde (6e). Ochre solid, 92% yield (1.87 g).
1
M.p. = 146-148 °C. H NMR (700 MHz, CDCl3) δ: 5.60 (s, 2H), 6.96 (d, J = 8.4 Hz, 1H),
7.10-7.13 (m, 1H), 7.54-7.57 (m, 1H), 7.62-7.64 (m, 1H), 7.67-7.70 (m, 1H), 7.92 (dd, J =
8.4, 2.1 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 9.1 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H),
ACS Paragon Plus Environment

Page 17 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
8.07 (dd, J = 8.4, 2.1 Hz, 1H), 8.58 (s, 1H), 10.65 (s, 1H). 13C NMR (100 MHz, CDCl3) δ:
71.0, 121.7, 123.4, 125.4, 127.2, 127.9, 128.8, 129.0, 129.1, 129.6, 130.0, 131.6, 132.4, 135.8,
136.0, 160.4, 189.6, 193.5. LRMS (ESI): Mass calcd for [M+Na]+ C19H14O3Na: 313.1; found
313.3. Anal. calcd for C19H14O3: C, 78.61; H, 4.86; Found: C, 78.72; H, 4.78.
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
2-(2-(4-Methoxyphenyl)-2-oxoethoxy)benzaldehyde (6f). Beige solid, 97% yield (1.83
g). M.p. = 130-131 °C. 1H NMR (700 MHz, CDCl3) δ: 3.92 (s, 3H), 5.40 (s, 2H), 6.90 (d, J =
8.4 Hz, 1H), 7.00-7.10 (m, 2H), 7.08-7.11 (m, 1H), 7.51-7.55 (m, 1H), 7.90 (dd, J = 7.7, 1.4
Hz, 1H), 8.01-8.03 (m, 2H), 10.62 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 56.6, 71.8, 113.8,
115.2 (2C), 122.6, 126.3, 128.2, 129.6, 131.5 (2C), 136.8, 161.4, 165.3, 190.6, 193.1. LRMS
(ESI): Mass calcd for [M+Na]+ C16H14O4Na: 293.1; found 293.3. Anal. calcd for C16H14O4: C,
71.10; H, 5.22; Found: C, 71.18; H, 5.34.
5-Methyl-2-(2-oxo-2-phenylethoxy)benzaldehyde (6g). Beige solid, 91% yield (1.62 g).
M.p. = 107-109 °C. 1H NMR (400 MHz, CDCl3) δ: 2.33 (s, 3H), 5.41 (s, 2H), 6.80 (d, J = 8.0
Hz, 1H), 7.32 (dd, J = 8.0, 4.0 Hz, 1H), 7.51-7.57 (m, 2H), 7.53-7.70 (m, 2H), 7.99-8.03 (m,
2H), 10.57 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 20.3, 71.0, 112.9, 125.0, 128.0 (2C),
128.7, 129.0 (2C), 131.2, 134.1, 134.3, 136.4, 158.5, 189.8, 193.8. LRMS (ESI): Mass calcd
for [M+Na]+ C16H14O3Na: 277.1; found 277.2. Anal. calcd for C16H14O3: C, 75.57; H, 5.55;
Found: C, 75.46; H, 5.43.
2-(2-(2,4-Dimethoxyphenyl)-2-oxoethoxy)benzaldehyde (6h). Pink solid, 87% yield
1
(1.83 g). M.p. = 111-113 °C. H NMR (700 MHz, CDCl3) δ: 3.92 (s, 3H), 3.99 (s, 3H), 5.37
(s, 2H), 6.53 (d, J = 2.1 Hz, 1H), 6.64 (dd, J = 2.1, 9.1 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H),
7.05-7.07 (m, 1H), 7.49-7.51 (m, 1H), 7.90 (dd, J = 7.7, 2.1 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H),
10.65 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 55.6, 55.7, 74.3, 98.1, 106.1, 113.0, 117.8,
121.0, 125.2, 128.3, 133.2, 135.6, 161.1, 161.4, 165.6, 190.0, 192.5. Mass calcd for [M+H]+
C17H17O5: 301.1; found 301.4. Anal. calcd for C17H16O5: C, 67.99; H, 5.37; Found: C, 68.06;
H, 5.33.
2-(2-(3,4-Difluorophenyl)-2-oxoethoxy)benzaldehyde (6i). Yellow solid, 86% yield
(1.66 g). M.p. = 138-141 °C. 1H NMR (700 MHz, CDCl3) δ: 5.39 (s, 2H), 6.90 (d, J = 8.4 Hz,
1H), 7.12-7.14 (m, 1H), 7.33-7.37 (m, 1H), 7.55 (dddd, J = 16.1, 8.4, 7.0, 2.1 Hz, 1H), 7.83-
7.85 (m, 1H), 7.88 (dddd, J = 18.2, 9.8, 7.0, 2.1 Hz, 1H), 7.91 (dd, J = 7.7, 2.1 Hz, 1H), 10.59
(s, 1H). 13C NMR (100 MHz, CDCl3) δ: 70.9, 112.7, 117.7 (dd, J = 18.2, 1.6 Hz), 118.0 (d, J
= 17.4 Hz), 122.0, 125.3 (dd, J = 7.1, 3.9 Hz), 125.4, 129.0, 131,7 (t, J = 4.7 Hz), 135.8, 150.7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 23
1
2
3
4
5
6
7
(dd, J = 250.4, 12.6 Hz), 154.1 (dd, J = 257.5, 12.6 Hz), 159.9, 189.3, 191.4. LRMS (ESI):
Mass calcd for [M+Na]+ C15H10F2O3Na: 299.1; found 299.2. Anal. calcd for C15H10F2O3: C,
65.22; H, 3.65; Found: C, 65.31; H, 3.61.
8
9
2-(2-([1,1'-Biphenyl]-4-yl)-2-oxoethoxy)benzaldehyde (6j). Beige solid, 97% yield (2.15
1
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
g). M.p. = 145-147 °C. H NMR (700 MHz, CDCl3) δ: 5.49 (s, 2H), 6.93 (d, J = 8.4 Hz, 1H),
7.11-7.13 (m, 1H), 7.45-7.47 (m, 1H), 7.51-7.56 (m, 3H), 7.66-7.68 (m, 2H), 7.77-7.79 (m,
2H), 7.92 (dd, J = 7.7, 2.1 Hz, 1H), 8.01-8.12 (m, 2H), 10.65 (s, 1H). 13C NMR (100 MHz,
CDCl3) δ: 71.0, 112.9, 121.7, 125.4, 127.3 (2C), 127.6 (2C), 128.6, 128.7 (2C), 128.8, 129.1
(2C), 132.9, 135.8, 139.5, 146.9, 160.3 189.6, 193.2. LRMS (ESI): Mass calcd for [M+Na]+
C21H16O3Na: 339.1; found 339.4. Anal. calcd for C21H16O3: C, 79.73; H, 5.10; Found: C,
79.67; H, 5.15.
Typical procedure for the NHC-catalyzed crossed intramolecular benzoin reactions
A flame dried round bottom flask was charged with triazolium salt 1d (10.8 mg, 0.015
mmol, 15 mol%) and 1.0 mL of cyclopentyl methyl ether (0.1 M). Then to this solution was
added BEMP (4.3 ꢀL, 0.015 mmol, 15 mol%) via syringe and the solution was allowed to stir
at ambient temperature for 30 minutes. After this time keto-aldehyde (0.1 mmol) was added
and the resulting solution was allowed to stir at ambient temperature and monitored by TLC.
The reaction mixture was placed directly onto a silica gel column and eluted with a suitable
solution of hexane and ethyl acetate (8:2). Evaporation of solvent afforded analytically pure
product.
(S)-3-Hydroxy-3-phenylchroman-4-one (7a).7a White solid, 99% yield (23.5 mg). M.p. =
77-79 °C. [α]D20 = −10.8 (c 1.8, CH2Cl2). Chiral HPLC analysis Phenomenex Lux Cellulose-1
(90:10 hexane/IPA, flow rate 0.7 mLmin-1, 254 nm, 25 °C) tR major (S) 16.4 min., tR minor
(R) 19.8 min., 93% ee. 1H NMR (400 MHz, CDCl3) δ: 4.18 (bs, 1H), 4.50 (d, J = 11.6 Hz,
1H), 4.88 (d, J = 11.6 Hz, 1H), 6.97-7.00 (m, 1H), 7.07-7.11 (m, 1H), 7.32-7.37 (m, 3H),
7.47-7.57 (m, 3H), 7.96 (dd, J = 8.0, 1.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 73.4, 73.8,
118.1, 119.2, 122.0, 126.0 (2C), 127.6, 128.7 (2C), 128.8, 136.8, 138.5, 161.6, 194.6. LRMS
(ESI): Mass calcd for [M+Na]+ C15H12O3Na: 263.1; found 263.3. Anal. calcd for C15H12O3: C,
74.99; H, 5.03; Found: C, 75.13; H, 5.08.
(S)-3-(4-Bromophenyl)-3-hydroxychroman-4-one (7b). Light yellow solid, 91% yield
20
(29.1 mg). M.p. = 98-101 °C. [α]D = −4.2 (c 1.2, CH2Cl2). Chiral HPLC analysis Chiralpak
ACS Paragon Plus Environment

Page 19 of 23
The Journal of Organic Chemistry
1
2
3
OJ (95:5 hexane/IPA, flow rate 0.7 mLmin-1, 254 nm, 25 °C) tR major (S) 36.7 min., tR minor
4
5
1
(R) 40.9 min., 92% ee. H NMR (400 MHz, CDCl3) δ: 4.24 (bs, 1H), 4.47 (d, J = 11.6 Hz,
6
7
8
9
1H), 4.81 (d, J = 11.6 Hz, 1H), 6.99 (d, J = 8.4, 0.8 Hz, 1H), 7.10 (ddd, J = 8.0, 7.2, 1.2 Hz,
1H), 7.35-7.38 (m, 2H), 7.44-7.48 (m, 2H), 7.55 (dddd, J = 15.6, 8.8, 7.2, 2.0 Hz, 1H), 7.94
(dd, J = 8.0, 1.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 73.0, 73.7, 118.1, 119.0, 122.2,
123.1, 127.7, 127.8 (2C), 131.9 (2C), 137.1, 137.6, 161.5, 194.0. LRMS (ESI): Mass calcd for
[M+Na]+ C15H11BrO3Na: 341.0; found 341.1. Anal. calcd for C15H11BrO3: C, 56.45; H, 3.47;
Found: C, 56.36; H, 3.36.
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
(S)-3-(4-Fluorophenyl)-3-hydroxychroman-4-one (7c). Yellow solid, 81% yield (20.6
20
mg). M.p. = 77-78 °C. [α]D = −4.4 (c 5.4, CH2Cl2). Chiral HPLC analysis Chiralpak OJ
(95:5 hexane/IPA, flow rate 0.7 mLmin-1, 254 nm, 25 °C) tR major (S) 37.7 min., tR minor (R)
1
42.3 min., 94% ee. H NMR (700 MHz, CDCl3) δ: 4.20 (bs, 1H), 4.45 (d, J = 11.2 Hz, 1H),
4.80 (d, J = 11.2 Hz, 1H), 6.97-7.02 (m, 3H), 7.07-7.09 (m, 1H), 7.43-7.47 (m, 2H), 7.53
(dddd, J = 15.4, 8.4, 7.7, 2.1 Hz, 1H), 7.92 (dd, J = 8.4, 2.1 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ: 73.0, 73.8, 115.7 (d, J = 21.3 Hz, 2C), 118.1, 119.0, 122.1, 127.7, 128.0 (d, J = 7.9
Hz, 2C), 134.3 (d, J = 4.0 Hz), 137.0, 161.4, 162.8 (d, J = 246.4 Hz), 194.3. LRMS (ESI):
Mass calcd for [M+Na]+ C15H11FO3Na: 281.1; found 281.2. Anal. calcd for C15H11FO3: C,
69.76; H, 4.29; Found: C, 69.68; H, 4.38.
(S)-3-Hydroxy-3-(4-(trifluoromethoxy)phenyl)chroman-4-one (7d). Light yellow oil,
91% yield (29.3 mg). [α]D20 = −4.6 (c 1.1, CH2Cl2). Chiral HPLC analysis Chiralpak OJ (98:2
hexane/IPA, flow rate 0.7 mLmin-1, 254 nm, 25 °C) tR minor (R) 34.0 min., tR major (S) 43.6
1
min., 90% ee. H NMR (700 MHz, CDCl3) δ: 4.26 (bs, 1H), 4.48 (d, J = 11.9 Hz, 1H), 4.80
(d, J = 11.9 Hz, 1H), 6.98 (dd, J = 8.4, 0.7 Hz, 1H), 7.10 (dt, J = 7.7, 0.7 Hz, 1H), 7.16 (dd, J
= 9.1, 0.7 Hz, 2H), 7.50-7.53 (m, 2H), 7.55 (dddd, J = 16.1, 9.1, 7.7, 2.1 Hz, 1H), 7.93 (dd, J
= 8.4, 2.1 Hz, 1H). 13C NMR (176 MHz, CDCl3) δ: 73.9, 74.8, 119.2, 119.9, 121.4 (q, J =
258.0 Hz), 122.0 (2C), 123.2, 128.7 (2C), 128.7, 138.1, 138.2, 150.4, 162.5, 195.0. LRMS
(ESI): Mass calcd for [M+Na]+ C16H11F3O4Na: 347.0; found 347.1. Anal. calcd for
C16H11F3O4: C, 59.27; H, 3.42; Found: C, 59.33; H, 3.51.
(S)-3-Hydroxy-3-(naphthalen-2-yl)chroman-4-one (7e). Ochre solid, 99% yield (28.5
20
mg). M.p. = 108-110 °C. [α]D = −7.5 (c 1.6, CH2Cl2). Chiral HPLC analysis Chiralpak OJ
(80:20 hexane/IPA, flow rate 0.7 mLmin-1, 254 nm, 25 °C) tR minor (R) 80.8 min., tR major
(S) 87.3 min., 95% ee. 1H NMR (400 MHz, CDCl3) δ: 4.34 (bs, 1H), 4.58 (d, J = 12.0 Hz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 23
1
2
3
4
5
6
7
8
9
1H), 5.03 (d, J = 12.0 Hz, 1H), 6.98-7.00 (m, 1H), 7.07-7.11 (m, 1H), 7.46-7.54 (m, 3H), 7.62
(dd, J = 8.8, 2.0 Hz, 1H), 7.77-7.82 (m, 2H), 7.84 (d, J = 8.8 Hz, 1H), 7.94 (m, 1H), 7.99 (dd,
J = 7.6, 0.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 73.6, 73.7, 118.1, 119.2, 122.0, 123.6,
125.5, 126.3, 126.7, 127.6, 127.7, 128.4, 128.7, 133.0, 132.3, 135.7, 136.9, 161.5, 194.6.
LRMS (ESI): Mass calcd for [M+Na]+ C19H14O3Na: 313.1; found 313.2. Anal. calcd for
C19H14O3: C, 78.61; H, 4.86; Found: C, 78.69; H, 4.95.
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
(S)-3-Hydroxy-3-(4-methoxyphenyl)chroman-4-one (7f).7a Yellow oil, 98% yield (26.4
20
mg). [α]D = −5.2 (c 4.6, CH2Cl2). Chiral HPLC analysis Chiralpak OJ (90:10 hexane/IPA,
flow rate 0.7 mLmin-1, 254 nm, 25 °C) tR minor (R) 66.4 min., tR major (S) 100.9 min., 94%
ee. 1H NMR (700 MHz, CDCl3) δ: 3.76 (s, 3H), 4.16 (bs, 1H), 4.44 (d, J = 11.9 Hz, 1H), 4.84
(d, J = 11.9 Hz, 1H), 6.83- 6.86 (m, 2H), 6.94 (d, J = 7.7 Hz, 1H), 7.04-7.07 (m, 1H), 7.38-
7.41 (m, 2H), 7.50 (dddd, J = 16.1, 9.1, 7.7, 1.4 Hz, 1H), 7.92 (dd, J = 7.7, 1.4 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ: 55.2, 73.1, 73.6, 114.1 (2C), 118.0, 119.2, 121.9, 127.4 (2C),
127.6, 130.3, 136.7, 159.9, 161.4, 194.7. LRMS (ESI): Mass calcd for [M+Na]+ C16H14O4Na:
293.1; found 293.2. Anal. calcd for C16H14O4: C, 71.10; H, 5.22; Found: C, 71.14; H, 5.33.
(S)-3-Hydroxy-6-methyl-3-phenylchroman-4-one (7g). Ochre solid, 98% yield (24.8
21
mg). M.p. = 98-99 °C. [α]D = −5.7 (c 1.1, CH2Cl2). Chiral HPLC analysis Chiralpak OJ
(90:10 hexane/IPA, flow rate 0.7 mLmin-1, 254 nm, 25 °C) tR minor (R) 44.5 min., tR major
(S) 59.1 min., 86% ee. 1H NMR (400 MHz, CDCl3) δ: 2.34 (bs, 3H), 4.22 (s, 1H), 4.46 (d, J =
11.6 Hz, 1H), 4.84 (d, J = 11.6 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 7.30-7.36 (m, 4H), 7.46-
7.52 (m, 2H), 7.74 (d, J = 2.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 20.4, 73.4, 73.9,
117.9, 118.8, 126.0 (2C), 127.1, 128.7 (2C), 128.8, 131.5, 138.0, 138.7, 159.7, 194.7. LRMS
(ESI): Mass calcd for [M+Na]+ C16H14O3Na: 277.1; found 277.2. Anal. calcd for C16H14O3: C,
75.57; H, 5.55; Found: C, 75.45; H, 5.42.
(S)-3-(2,4-Dimethoxyphenyl)-3-hydroxychroman-4-one (7h). Light yellow solid, 97%
20
yield (29.0 mg). M.p. = 108-110 °C. [α]D = +4.4 (c 1.4, CH2Cl2). Chiral HPLC analysis
Chiralcel OD-H (90:10 hexane/IPA, flow rate 0.7 mLmin-1, 254 nm, 25 °C) tR major (S) 21.3
1
min., tR minor (R) 65.7 min., 82% ee. H NMR (700 MHz, CDCl3) δ: 3.70 (s, 3H), 3.78 (s,
3H), 3.83 (bs, 1H), 4.30 (d, J = 11.9 Hz, 1H), 4.92 (d, J = 11.9 Hz, 1H), 6.45-6.48 (m, 2H),
6.95 (d, J = 9.1 Hz, 1H), 7.04-7.06 (m, 1H), 7.41 (d, J = 9.1 Hz, 1H), 7.46-7.48 (m, 1H), 7.94
(dd, J = 7.7, 2.1 Hz, 1H). 13C NMR (176 MHz, CDCl3) δ: 56.4, 56.6, 74.7, 75.1, 100.7, 105.8,
118.8, 120.1, 121.0, 122.8, 128.8, 129.4, 136.7, 159.0, 161.9, 162.3, 193.7. LRMS (ESI):
ACS Paragon Plus Environment

Page 21 of 23
The Journal of Organic Chemistry
1
2
3
4
5
Mass calcd for [M+Na]+ C17H16O5Na: 323.1; found 323.3. Anal. calcd for C17H16O5: C, 67.99;
H, 5.37; Found: C, 68.12; H, 5.48.
6
7
(S)-3-(3,4-Difluorophenyl)-3-hydroxychroman-4-one (7i). Yellow solid, 82% yield (22.6
8
9
20
mg). M.p. = 100-101 °C. [α]D = −2.6 (c 1.7, CH2Cl2). Chiral HPLC analysis Chiralpak OJ
(97:3 hexane/IPA, flow rate 0.7 mLmin-1, 254 nm, 25 °C) tR major (S) 47.3 min., tR minor (R)
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
53.2 min., 90% ee. H NMR (700 MHz, CDCl3) δ: 4.22 (bs, 1H), 4.45 (d, J = 11.2 Hz, 1H),
4.75 (d, J = 11.2 Hz, 1H), 6.99 (d, J = 9.1 Hz, 1H), 7.08-7.12 (m, 2H), 7.18-7.21 (m, 1H),
7.35 (dddd, J = 2.1, 7.7, 11.2, 18.9 Hz, 1H), 7.55-7.57 (m, 1H), 7.92 (dd, J = 7.7, 2.1 Hz, 1H).
13C NMR (176 MHz, CDCl3) δ: 73.6, 74.8, 116.6 (d, J = 19.4 Hz), 118.5 (d, J = 16.7 Hz),
119.2, 119.8, 123.3 (m), 123.4, 128.8, 136.7 (t, J = 4.0 Hz), 138.3, 151.3 (dd, J = 248.3, 12.3
Hz), 151.5 (dd, J = 251.0, 12.5 Hz), 162.4, 194.6. LRMS (ESI): Mass calcd for [M+Na]+
C15H10F2O3Na: 299.0; found 299.2. Anal. calcd for C15H10F2O3: C, 65.22; H, 3.65; Found: C,
65.34; H, 3.53.
(S)-3-([1,1'-Biphenyl]-4-yl)-3-hydroxychroman-4-one (7j). Light yellow solid, 98%
20
yield (29.9 mg). M.p. = 97-99 °C. [α]D = −4.2 (c 1.2, CH2Cl2). Chiral HPLC analysis
Chiralpak OJ (90:10 hexane/IPA, flow rate 1.0 mLmin-1, 254 nm, 25 °C) tR major (S) 37.0
min., tR minor (R) 42.2 min., 96% ee. 1H NMR (700 MHz, CDCl3) δ: 4.20 (bs, 1H), 4.51 (d, J
= 11.9 Hz, 1H), 4.91 (d, J = 11.9 Hz, 1H), 6.99 (d, J = 7.7 Hz, 1H), 7.08-7.11 (m, 1H), 7.32-
7.35 (m, 1H), 7.40-7.43 (m, 2H), 7.52-7.54 (m, 3H), 7.55 (m, 4H), 7.96 (dd, J = 8.4, 1.4 Hz,
1H). 13C NMR (100 MHz, CDCl3) δ: 73.3, 73.8, 118.1, 119.2, 122.1, 126.5 (2C), 127.1 (2C),
127.5 (2C), 127.6, 127.7, 128.8 (2C), 136.9, 137.4, 140.4, 141.7, 161.6, 194.5. LRMS (ESI):
Mass calcd for [M+Na]+ C21H16O3Na: 339.1; found 339.2. Anal. calcd for C21H16O3: C, 79.73;
H, 5.10; Found: C, 79.80; H, 5.17.
Supporting Information
Copies of 1H and 13C spectra for all new compounds, HPLC scans and X-ray crystallographic
data of compound 1a. This material is available free of charge via the Internet at
http://pubs.acs.org.
ACKNOWLEDGMENTS
We gratefully acknowledge the National Science Centre (Grant No. UMO-
2011/03/D/ST5/05626) for financial support.
REFERENCES
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 23
1
2
3
4
5
6
7
(1) For reviews see: (a) Masters, K.-S.; Bräse, S. Chem. Rev. 2012, 112, 3717−3776. (b)
Gaspar, A.; Matos, M. J.; Garrido, J.; Uriarte, E.; Borges F. Chem. Rev. 2014, 114,
4960−4992.
8
9
(2) (a) Elsinghorst, P. W.; Cavlar, T.; Müller, A.; Braune, A.; Blaut M.; Gütschow M. J. Nat.
Prod. 2010, 74, 2243−2249. (b) Dai, Y.; Harinantenaina, L.; Brodie P. J.; Goetz, M.; Shen Y.;
TenDyke, K.; Kingston, D. G. I. J. Nat. Prod. 2013, 76, 865−872. (c) Siddiqui, I. N.; Zahoor,
A.; Hussain H.; Ahmed, I.; Ahmad, V. U.; Padula, D.; Draeger S.; Schulz, B.; Meier, K.;
Steinert, M.; Kurtán, T.; Flörke, U.; Pescitelli, G.; Krohn, K. J. Nat. Prod. 2011, 74, 365−373.
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) Hachisu, Y.; Bode, J. W.; Suzuki, K. J. Am. Chem. Soc. 2003, 125, 8432−8433.
(4) Enders, D.; Niemeier, O.; Balensiefer, T. Angew. Chem. Int. Ed. 2006, 45, 1463−1467.
(5) For recent reviews, see: (a) Chiang, P.-C.; Bode, J. W. TCI MAIL 2011, 149, 2−17. (b)
Vora, H. U.; Rovis, T. Aldrichimica Acta 2011, 44, 3−11. (c) Biju, A. T.; Kuhl, N.; Glorius, F.
Acc. Chem. Res. 2011, 44, 1182−1195. (d) Hirano, K.; Piel, I.; Glorius, F. Chem. Lett. 2011,
40, 786−791. (e) Nair, V.; Menon, R. S.; Biju, A. T.; Sinu, C. R.; Paul, R. R.; Jose, A.;
Sreekumar, V. Chem. Soc. Rev. 2011, 40, 5336−5346. (f) Rong, Z.-Q.; Zhang, W.; Yang, G.-
Q.; You, S.-L. Curr. Org. Chem. 2011, 15, 3077−3090. (g) Cohen, D. T.; Scheidt, K. A.
Chem. Sci. 2012, 3, 53−57. (h) Grossmann, A.; Enders, D. Angew. Chem., Int. Ed. 2012, 51,
314−325. (i) Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511−3522. (j) Vora, H. U.;
Wheeler, P.; Rovis, T. Adv. Synth. Catal. 2012, 354, 1617−1639. (k) Douglas, J.; Churchill,
G.; Smith, A. D. Synthesis 2012, 44, 2295−2309. (l) Izquierdo, J.; Hutson, G. E.; Cohen, D.
T.; Scheidt, K. A. Angew. Chem., Int. Ed. 2012, 51, 11686−11698. (m) Hopkinson, M. N.;
Richter, C.; Schedler, M.; Glorius, F. Nature, 2014, 510, 485−496. (n) Mahatthananchai, J.;
Bode, J. W. Acc. Chem. Res. 2014, 47, 696–707. (o) Ryan, S. R.; Candish, L.; Lupton, D. W.
Chem. Soc. Rev. 2013, 42, 4906−4917. For selected asymmetric benzoin reactions, see: (aa)
Enders, D.; Breuer, K.; Teles, J. H. Helv. Chim. Acta 1996, 79, 1217−1221. (ab) Enders, D.;
Kallfass, U. Angew. Chem., Int. Ed. 2002, 41, 1743−1745. (ac) Ma, Y.-J.; Wei, S.-P.; Wu, J.;
Yang, F.; Liu, B.; Lan, J.-B.; Yang, S.-Y.; You, J.-S. Adv. Synth. Catal. 2008, 350,
2645−2651. (ad) Huang, X.; Ye, S. Chin. Sci. Bull. 2010, 55, 1753−1757. (ad) O’Toole, S. E.;
Rose, C. A.; Gundala, S.; Zeitler, K.; Connon, S. J. J. Org. Chem. 2011, 76, 347−357. (ae)
Soeta, T.; Tabatake, Y.; Inomata, K.; Ukaji, Y. Tetrahedron 2012, 68, 894−899. For
enantioselective aldehyde−ketone benzoin reactions, see: (af) Enders, D.; Niemeier, O. Synlett
2004, 2111−2114. (ag) Enders, D.; Niemeier, O.; Balensiefer, T. Angew. Chem., Int. Ed.
ACS Paragon Plus Environment

Page 23 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2006, 45, 1463−1467. (ah) Enders, D.; Niemeier, O.; Raabe, G. Synlett 2006, 2431−2434. (ai)
Takikawa, H.; Hachisu, Y.; Bode, J. W.; Suzuki, K. Angew. Chem., Int. Ed. 2006, 45,
3492−3494. (aj) Enders, D.; Grossmann, A.; Fronert, J.; Raabe, G. Chem. Commun. 2010,
6282−6284. (ak) Rose, C. A.; Gundala, S.; Fagan, C.-L.; Franz, J. F.; Connon, S. J.; Zeitler,
K. Chem. Sci. 2012, 3, 735−740.
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
(6) Takikawa, H.; Suzuki, K. Org. Lett. 2007, 9, 2713−2716.
(7) (a) Li, Y.; Feng, Z.; You, S.-L. Chem. Commun. 2008, 2263−2265. (b) Jia, M.-Q.; You,
S.-L. ACS Catal. 2013, 3, 622−624.
(8) (a) Li, Y.; Wang, X.-Q.; You, S.-L. Chem. Commun. 2009, 5823−5825. (b) Rong, Z.-Q.;
Li, Y.; Yang, G.-Q.; You, S.-L. Synlett 2011, 1033−1037. (c) Rong, Z.-Q.; Jia, M.-Q.; You,
S.-L. Org. Lett. 2011, 13, 4080−4083. (d) Jia, M.-Q.; Li, Y.; Rong, Z.-Q.; You, S.-L. Org.
Biomol. Chem. 2011, 9, 2072−2074.
(9) Jia, M.-Q.; You, S.-L. Chem. Commun. 2012, 48, 6363−6365.
(10) (a) Rafiński, Z.; Kozakiewicz, A.; Rafińska, K. ACS Catal. 2014, 4, 1404−1408. (b)
Rafiński, Z.; Kozakiewicz, A.; Rafińska, K. Tetrahedron 2014, 70, 5739−5745.
(11) Bosiak, M. J.; Pakulski, M. M. Synthesis, 2011, 43, 316−324.
(12) Vora, H. U.; Lathrop, S. P.; Reynolds, N. T.; Kerr, M. S.; Read de Alaniz, J.; Rovis, T
Org. Synth. 2010, 87, 350.
(13) Struble, J. R.; Bode, J. W. Org. Synth. 2010, 87, 362.
(14) The structural data have been deposited with Cambridge Crystallographic Data Centre,
the CCDC numbers (CCDC 1005945).
(15) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418-8420.
(16) Moore, J. L.; Silvestri, A. P.; Read de Alaniz, J.; DiRocco, D. A.; Rovis, T. Org. Lett.
2011, 13, 1742-1745.
ACS Paragon Plus Environment