Chiral pyrophosphoric acid catalysts for the para-selective and enantioselective aza-friedel-crafts reaction of phenols

Article abstract of DOI:10.1055/s-0037-1610250

Chiral BINOL-derived pyrophosphoric acid catalysts were developed and used for the regio- and enantioselective aza-Friedel-Crafts reaction of phenols with aldimines. ortho/para-Directing phenols could react at the para-position selectively with moderate to good enantioselectivities. Moreover, the gram-scale transformation of a product into the key intermediate for the antifungal agent (R)-bifonazole was demonstrated.

Full text of DOI:10.1055/s-0037-1610250

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
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en
H. Okamoto et al.
Feature
Synthesis
Chiral Pyrophosphoric Acid Catalysts for the para-Selective and
Eanantioselective Aza-Friedel–Crafts Reaction of Phenols
Haruka Okamotoa
Kohei Toha
Takuya Mochizukia
Hidefumi Nakatsujia
Akira Sakakura*b
Manabu Hatano*a
Kazuaki Ishihara*a
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a Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa,
Nagoya 464-8603, Japan
hatano@chembio.nagoya-u.ac.jp
ishihara@cc.nagoya-u.ac.jp
b Graduate School of Natural Science and Technology, Okayama University,
3-1-1 Tsushimanaka, Kita-ku, Okayama 700-8530, Japan
sakakura@okayama-u.ac.jp
Received: 27.06.2018
Accepted after revision: 24.07.2018
Published online: 22.08.2018
tion of (R)-2 successfully provided the corresponding (R)-3
(Scheme 1).7 Fortunately, since chiral pyrophosphoric acids
(R)-3 are not very sensitive to moisture, we envisioned that
a suitable catalytic system could make the best use of the
possible double acid-base cooperative function of novel (R)-3.
DOI: 10.1055/s-0037-1610250; Art ID: ss-2018-e0435-fa
Abstract Chiral BINOL-derived pyrophosphoric acid catalysts were de-
veloped and used for the regio- and enantioselective aza-Friedel–Crafts
reaction of phenols with aldimines. ortho/para-Directing phenols could
react at the para-position selectively with moderate to good enantiose-
lectivities. Moreover, the gram-scale transformation of a product into
the key intermediate for the antifungal agent (R)-bifonazole was
demonstrated.
Acid
Base
Ar
Ar
OH
Stronger
acid
O
P
P
O
O
OH
P
O
H
O
(COCl)2, DMF
O
H
O
CH2Cl2, 40 °C, 5 min
O
P
OH
O
O
Key words Brønsted acid, phosphoric acid, pyrophosphoric acid, or-
ganocatalyst, aza-Friedel–Crafts reaction, phenol, regio-selectivity
>99% yield
O
Stronger
acid
OH
Ar
Ar
Base
Acid
(R)-2
(R)-3
Double acid–base pairs
Double acid moieties
Pyrophosphoric acid (H4P2O7) is a dehydrative conden-
sate of phosphoric acid (H3PO4) and is frequently provided
in vivo as magnesium(II), calcium(II), and alkali metal(I) py-
rophosphates from adenosine triphosphate (ATP).1 Remark-
ably, pyrophosphoric acid (pKa1(H2O) = 0.91, pKa2(H2O) =
2.10) is a stronger acid than phosphoric acid [pKa1(H2O) =
2.16, pKa2(H2O) = 7.21].2 Indeed, even pKa2 of pyrophos-
phoric acid is lower than pKa1 of phosphoric acid. Despite
its potential as a strong diprotic acid motif for new chiral
organocatalysts, to the best of our knowledge, a chiral pyro-
phosphoric acid has not yet been developed for asymmetric
catalysis. In this regard, chiral BINOL (1,1′-bi-2-naphthol)-
derived phosphoric acids 1 have been shown to be highly
practical and powerful catalysts for a variety of asymmetric
reactions.3,4 Moreover, several BINOL-derived bis(phos-
phoric acid)s have recently been developed by Gong,5 Mo-
miyama/Terada,6 and our group.7 In particular, our recent
chiral bis(phosphoric acid)s (R)-27 were highly effective for
the enantioselective aza-Friedel–Crafts (aza-FC) reaction of
2-methoxyfuran8 with α-ketimino esters. During the course
of our previous study, we found that dehydrative condensa-
Scheme 1 Preparation of chiral pyrophosphoric acids (R)-3
In this study, we have developed a regio- and enantiose-
lective aza-FC reaction9 of phenols 510,11 with aldimines 4
through the use of chiral BINOL-derived pyrophosphoric ac-
ids (R)-3 (Scheme 2a). In this reaction, the catalyst should
control both the regio-selectivity of 5 (i.e., para- and ortho-
control of 5 leading to 6 and 7, respectively) and the enan-
tioface-selectivity of 4.
Although simple phenols have an ortho/para-orienta-
tion,12 ortho-addition is often preferred, particularly for ba-
sic carbonyl compounds due to the inherent directing prop-
erties of acidic phenols,10 as seen in the traditional Betti re-
action13 between phenols, aldehydes, and amines (Scheme
2b). Therefore, the para-selective catalytic asymmetric FC
reaction of phenols has been very limited.11 Moreover, in
spite of the interesting remote regio-control by the asym-
metric catalytic system, there has been no previous report
on the reason or strategy for the prioritization of para-se-
lectivity.11 In this context, we were interested in the remote
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

B
H. Okamoto et al.
Feature
Synthesis
Biographical Sketches
Haruka Okamoto was born in Aichi,
Japan, in 1989. He received his BS
(2012) and MS (2014) degrees from
Nagoya University under the supervi-
sion of Prof. Kazuaki Ishihara. Since
2017, he is working at Mitsui Chemi-
cals Agro, Inc. as a researcher and his
current research area includes the
field of manufacturing technology of
agricultural chemicals.
Kohei Toh was born in Fukuoka, Ja-
pan, in 1995. He received his BS
(2018) degree from Nagoya Universi-
ty under the supervision of Prof. Ka-
zuaki Ishihara. He is currently a Master
course student in Ishihara’s group.
Takuya Mochizuki was born in Shi-
zuoka, Japan, in 1993. He received his
BS (2015) and MS (2017) degrees
from Nagoya University under the su-
pervision of Prof. Kazuaki Ishihara. He
is currently a Doctor course student in
Ishihara’s group.
Hidefumi Nakatsuji was born in
1981, Japan, and received his Ph.D.
from Kwansei Gakuin University in
2010 under the direction of Prof. Yoo
Tanabe. After postdoctoral studies in
Ishihara’s group at Nagoya University
for five years, he joined Prof. Yoo Ta-
nabe’s group at Kwansei Gakuin Uni-
versity as an assistant professor in
2015. Since 2018, he is working at Ta-
oka Chemical Co., Ltd. as a chief re-
search associate, and his current
research area includes the field of or-
ganic synthetic chemistry and process
chemistry.
Akira Sakakura was born in Mie, Ja-
pan, in 1970, and received his Ph.D.
from Nagoya University in 2000 under
the direction of Prof. Yoshihiro Haya-
kawa. After postdoctoral studies with
Prof. Shizuaki Murata at Nagoya Uni-
versity for nine months beginning in
2000, he joined Prof. Hideo Kigoshi’s
group at the University of Tsukuba as
an assistant professor in 2001. In
2003, he joined Prof. Ishihara’s group
at Nagoya University as an associate
professor. He was appointed professor
at Okayama University in 2012. His re-
search interests include development
of efficient methods for synthesis of
bioactive natural products and design
of asymmetric catalysts based on
acid-base combination chemistry.
Manabu Hatano was born in Tokyo,
Japan, in 1975, and received his Ph.D.
from the Tokyo Institute of Technolo-
gy in 2003 under the direction of Prof.
Koichi Mikami. He was a JSPS Fellow
under the Japanese Junior Scientists
Program from 2000 to 2003. In 2003,
he joined Ishihara’s group at Nagoya
University as an assistant professor,
and became associate professor in
2007. His research interests include
the development of asymmetric catal-
ysis based on new design of acid–base
cooperative catalysts and supramo-
lecular catalysts.
Kazuaki Ishihara was born in Aichi,
Japan, in 1963, and received his Ph.D.
from Nagoya University in 1991 under
the direction of Prof. Hisashi Yama-
moto. He had the opportunity to work
under the direction of Prof. Clayton H.
Heathcock at the University of Califor-
nia, Berkeley, as a visiting graduate
student for three months in 1988. He
was a JSPS Fellow under the Japanese
Junior Scientists Program from 1989
to 1991. After he completed his post-
doctoral studies with Prof. E. J. Corey
at Harvard University (15 months be-
ginning in 1991), he returned to Japan
and joined Yamamoto’s group at Na-
goya University as an assistant profes-
sor in 1992, and became associate
professor in 1997. In 2002, he was ap-
pointed to his current position as a full
professor at Nagoya University. His re-
search interests include asymmetric
catalysis, biomimetic catalysis in-
duced by artificial enzymes, dehydra-
tive condensation catalysis toward
green and sustainable chemistry,
acid-base combination chemistry, and
designer supramolecular acid-base
combined catalysts.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

C
H. Okamoto et al.
Feature
Synthesis
control of para-selectivity of 5 with aldimines 4 in the pres-
ence of the novel catalysts (R)-3. We cannot completely
deny that two P(=O)OH sites in (R)-3 might act inde-
pendently and activate 4 and 5. However, unlike a reaction
using (R)-1, which can promote the ortho-addition of 5 to 4
(Scheme 2c),14 a reaction through the single P(=O)OH site of
(R)-3 might be geometrically disfavored due to the steric
hindrance of the 3,3′-moieties of (R)-3, and we strongly en-
visioned that 4 and 5 would be activated respectively on ei-
ther site of the P(=O)OH moieties (Scheme 2d). Overall,
with the use of (R)-3, normally difficult para-addition of 5
to 4 might be exclusive, since the ortho-positions of 5
would be far from the imino-carbon of 4.
We initially examined the reaction of phenol 5a with al-
dimine 4a through the use of achiral Brønsted acid catalysts
(5 mol%) in chloroform (0.1 M based on 5a) at 25 °C (Table
1). As a result, carboxylic acid catalysts, which are more or
less acidic than phosphoric acids, gave 6a and 7a in low
yields under such mild conditions (Table 1, entries 1, 2, 4, 5,
and 7). Although much more acidic sulfonic acids greatly
promoted the conversion of 5a, many unknown polar by-
products were obtained due to overreaction/decomposition
via 4a and/or 5a (entries 8 and 9).15 In contrast, phosphoric
acids, which have not only an acid function (POH) but also a
conjugate base function (P=O), did not give any by-prod-
ucts, although the catalytic activity was moderate, and
meaningful regio-selectivity (i.e., 6a vs 7a) was not ob-
served (entries 3 and 6). Overall, we found that phosphoric
acids with the bifunctional acid-base moieties would be
suitable for promoting the present reaction efficiently
without side reactions.
NHR2
R1
NHR2
(a)
OH
R2
N
catalyst
R1
HO
+
+
R1
H
OH
6
7
4
5a
(b)
NHR2
H
M
H
NR2
O
NR2
O
R1
HO
or
R1
H
R1
H
7
(M = H+ or Lewis acid)
Betti reaction product
(c) ortho-Selective reaction
(Shao, ref. 10n)
Ar
R2
N
H
H
O
O
O
O
R1
P
H
O
far
Ar
(R)-1·4·5a
para-Pathway is far.
ortho-Pathway is more favored.
(d) para-Selective reaction (This work)
R2
H
Ar
N
O
P
H
R1
O
O
O
far
P
O
O
H
O
O
H
Ar
(R)-3·4·5a
ortho-Pathway is far.
para-Pathway is more favored.
Scheme 2 Strategy for the regio- and enantioselective aza-Friedel–
Crafts reaction of phenols with aldimines
Table 1 Screening of Achiral Brønsted Acid Catalystsa
CO2Me
CO2Me
HN
HN
HO
CO2Me
N
catalyst (5 mol%)
+
+
PhOH
Ph
Ph
CHCl3 (0.1 M)
Ph
H
25 °C, 0.5–18 h
OH
4a (1.5 equiv)
5a
6a
7a
Entry
Catalyst
pKa in H2O
Reaction time (h) Conversion (%) of 5a
Yield (%) of 6a
Yield (%) of 7a
1
2
3
4
5
6
7
8
9
MeCO2H
4.76
2.86
1.42
1.24
0.65
0.26
0.26
–1.34
–13.0
18
18
18
18
18
18
18
0
0
0
0
0
0
CH2BrCO2H
PhOP(=O)(OH)2
CHF2CO2H
40
0
25
0
15
0
CCl3CO2H
16
24
8
2
14
9
(PhO)2P(=O)OH
CF3CO2H
15
6
2
p-MeC6H4SO3H
CF3SO3H
0.5
0.5
>99
>99
45
53
11
7
a The reactions were carried out with catalyst (5 mol%), 4a (1.5 equiv), and 5a (1 equiv) in CHCl3 (0.1 M based on 5a) at 25 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

D
H. Okamoto et al.
Feature
Synthesis
Next, we examined the use of chiral phosphoric acids
(R)-1a–c, chiral bis(phosphoric acid) (R)-2a, and chiral pyro-
phosphoric acids (R)-3a–c (Table 2). As a result, although
catalysts (R)-1a and (R)-1b promoted the reaction, the de-
sired 6a was obtained in low yields with low enantioselec-
tivities, along with undesired 7a (Table 2, entries 1 and 2).
The reaction did not proceed with the use of highly regard-
ed chiral phosphoric acid (R)-1c (TRIP),16 which would be
less acidic and sterically more hindered than (R)-1a and
(R)-1b (entry 3). Moreover, catalyst (R)-2a,7 which has
stronger acidity and much weaker basicity than (R)-1a,
showed lower catalytic activity than (R)-1a (entry 4). In
sharp contrast, as a novel stronger acid catalyst with a con-
jugate base function, chiral pyrophosphoric acid (R)-3a dra-
matically facilitated the reaction, and 6a was obtained in
82% yield with 52% ee within 30 minutes (entry 5).
Table 2 Screening of Chiral Brønsted Acid Catalystsa
CO2Me
CO2Me
HN
catalyst
HN
CO2Me
N
(5 mol%)
+
+
Ph
Ph
PhOH
(R)
CHCl3 (0.1 M)
Ph
H
OH
HO
25 °C, 0.5–18 h
4a (1.5 equiv)
5a
6a
CF3
7a
i-Pr
i-Pr
Ph
i-Pr
Ph
CF3
O
O
O
P
O
O
O
O
O
P
P
OH
Ph
OH
CF3
O
OH
i-Pr
i-Pr
(R)-1a
(R)-1b
(R)-1c
Ph
CF3
i-Pr
As entry 5 in Table 2 shows, the catalyst (R)-3a provided
at that time 7a in only 1% yield. The substituent effect at the
3,3′-positions of the binaphthyl backbone was important,
and sterically less hindered (R)-3b and (R)-3c showed much
lower catalytic activity than (R)-3a (Table 2, entries 6 and
7). Moreover, much stronger Brønsted acids, such as chiral
phosphoramide (R)-817 and chiral disulfonic acid (R)-918
also facilitated the reaction and the substrates were con-
sumed within 30 minutes (entries 8 and 9). However, the
enantiocontrol was hardly achieved and many unknown
polar by-products were generated. The tendency of the re-
sults in Table 2 was mostly similar to that with achiral cata-
lysts in Table 1; the sterically-optimized chiral catalysts
should have both appropriate acid and base functions to
promote the desired reaction.19
Ph
Ph
Ph
OH
Ph
O
P
O
P
P
P
O
O
O
O
O
O
OH
OH
O
H
O
O
H
O
O
O
P
P
OH
OH
Ph
O
O
OH
Ph
(R)-2a
(R)-3a
i-Pr
(R)-3b
Ph
Ph
i-Pr
Ph
Ph
O
Ph
Ph
O
O
i-Pr
OH
O
P
O
O
O
After further optimization of the reaction conditions,20–22
a reaction in diluted chloroform (0.01 M based on 5a) at
lower temperature (0 °C) improved both the yield and en-
antioselectivity of 6a up to 63% ee (Scheme 3a). Interesting-
ly, the enantioselectivity was greatly improved when o-
cresol (5b) was used instead of phenol (5a), and para-ad-
duct 6b was obtained as a sole product in 93% yield with
82% ee without the generation of ortho-adduct 7b (Scheme
3b). Notably, (R)-3a was detected almost intact in the re-
sulting reaction mixture,23 and recovered as (R)-2a through
silica gel column chromatography. In contrast, (R)-1a and
(R)-2a were not effective at that time, and the reaction
hardly proceeded under the same reaction conditions or
even at 25 °C (Scheme 3b). Moreover, as another control ex-
periment, 100 mol% of trichloroacetic acid as an achiral cat-
alyst also could not promote the reaction at 0 °C, and ulti-
mately promoted the reaction at 25 °C. However, a mean-
ingful regio-selectivity for 6b and 7b was not observed as
expected. Therefore, the observed para-selective reactions
with (R)-3a did not depend on ortho-substituted phenol 5b.
SO3H
SO3H
P
P
NHTf
i-Pr
OH
O
i-Pr
Ph
Ph
(R)-3c
(R)-8
(R)-9
i-Pr
Entry Catalyst
Reaction Yield (%) ee (%) of Yield(%)of ee (%) of
time (h) of 6a 6a 7a 7a
1
2
3
4
5
6
7b
8
9
(R)-1a
(R)-1b
(R)-1c
(R)-2a
(R)-3a
(R)-3b
(R)-3c
(R)-8
3
40
16
0
0
4
12
0
3
7
7
–
18
3
–
23
52
4
0
15
82
41
4
10
1
0
0.5
0.5
0.5
0.5
0.5
–
0
–
–3
3
0
–
50
61
26
12
11
10
(R)-9
2
a The reactions were carried out with catalyst (5 mol%), 4a (1.5 equiv), and
5a (1 equiv, 0.20 mmol) in CHCl3 (0.1 M based on 5a) at 25 °C.
b (S)-6a was obtained with 3% ee.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

E
H. Okamoto et al.
Feature
Synthesis
(a)
CO2Me
CO2Me
HN
CO2Me
HN
CO2Me
HN
OH
OH
(R)-3a
HN
HO
CO2Me
CO2Me
N
N
R
R
(5 mol%)
+
(R)-3a (5 mol%)
Ar
+
+
Ar
+
Ph
(R)
Ph
CHCl3 (0.01 M)
Ar
H
Ph
H
CHCl3 (0.01 M)
0 °C, 3 h
OH
HO
OH
0 °C, 3 h
5
4 (1.5 equiv)
6
4a (1.5 equiv)
5a
6a
90%, 63% ee
7a
R
7, 0%
0%
Products 6, yield, and enantioselectivity:
CO2Me CO2Me
(b)
CO2Me
CO2Me
CO2Me
OH
HN
HN
HO
HN
HN
HN
catalyst
CO2Me
N
Me
Me
(5 mol%)
Me
Ph
Ph
+
Ph
Ph
(R)
+
Ph
H
CHCl3 (0.01 M)
OH
OH
OH
Me
OH
0 °C, 3 h
6b, 93%, 82% ee (90% ee)b
Me
7b
0%
6a, 90%, 63% ee
[6a, 2%; 7a, 14%]a
4a (1.5 equiv)
5b
6b
6c, 58%, 77% ee (86% ee)b
[6b, 31%; 7b, 17%]a
[6c, 20%; 7c, 30%]a
(R)-3a:
(R)-2a:
(R)-1a:
93%, 82% ee
[6b, 78%, 79% ee]c
0%
0%
0%
0%
17%
0%
0%
1%
0%
31%
CO2Me
CO2Me
CO2Me
HN
HN
HN
(R)-1a (25 °C, 3 h):
I
CCl3CO2H (100 mol%, 0 °C, 3 h):
CCl3CO2H (100 mol%, 25 °C, 5 h):
Ph
Ph
OH
OH
OH
Scheme 3 Further optimization of the reaction conditions and the
para-selective reaction with o-cresol 5b
6d, 67%, 60% ee (90% ee)b
[6d, 9%; 7d, 29%]a
6e, 66%, 76% ee
6f, 11%, 26% ee
[6e, 30%; 7e, 20%]a
[6f, 1%; 7f, 21%]a
CO2Me
HN
CO2Me
HN
CO2Me
HN
With the optimized reaction conditions in hand, we
next examined the scope of phenols 5 with aldimines 4
(Scheme 4). As a result, not only phenyl-, but also p-tolyl-
and 1-naphthylaldimines were used, and the corresponding
para-adducts 6c and 6d were exclusively obtained with 77%
ee and 60% ee, respectively. Moreover, o-cresol (5b) and 2-
allylphenol reacted with 4a, and 6b and 6e were obtained
with 82% ee and 76% ee, respectively.
SiMe3
Me
OH
Me
OH
Ph
OH Me
Br
6g, 55%, 60% ee
6h, 93%, 67% ee
[6h, 12%; 7h, 5%]a
6i, 99%, 28% ee
[6i, 10%; 7i, 4%]a
[6g, 0%; 7g, 5%]a
CO2Me
CO2Me
HN
CO2Me
HN
HN
Me
OH
Me
Me
OH
S
OH
The amount of catalyst (R)-3a could be reduced to 1
mol%, and 6b was then obtained in 78% yield with 79% ee.
Unfortunately, 2-iodophenol gave 6f in low yield with low
enantioselectivity (26% ee). In contrast, bulky o-(trimethyl-
silyl)phenol was tolerable, and 6g was obtained with mod-
erate enantioselectivity (60% ee). Moreover, other aryl aldi-
mines were also examined with the use of o-cresol (5b). As
a result, p-tolyl, 1-naphthyl, and 2-naphthyl substrates
could be used, and good enantioselectivities (67–77% ee)
were observed in the corresponding para-adducts 6h, 6j,
and 6k. On the other hand, 4-bromophenyl and 2-thienyl
moieties decreased the enantioselectivities (see 6i and 6l).
Some products in Scheme 4 were crystalline, and a single
recrystallization effectively increased the enantiopurity
(see superscript footnote b for 6b, 6c, and 6d).24 Overall, the
observed enantioselectivities in Scheme 4 were not excel-
lent and further improvements are needed. However, it
should be noted that ortho-adducts 7 were not obtained in
any of the cases examined with (R)-3a in Scheme 4 (also
see superscript footnote a in Scheme 4 for the results with
CCl3CO2H (100%) at 25 °C for 5 h),25 and this might be a pio-
neering result for the normally difficult para-selective aza-
FC reaction of phenols.11
6j, 82%, 77% ee
6k, 74%, 68% ee
6l, 80%, 49% ee
[6l, 43%; 7l, 7%]a
[6k, 23%; 7k, 23%]a
[6j, 31%; 7j, 36%]a
Scheme 4 Scope of substrates in the regio- and enantioselective aza-
FC reaction of phenols. Reagents and conditions: (R)-3a (5 mol%), 4 (1.5
equiv), and 5 (1 equiv, 0.20 mmol) in CHCl3 (0.01 M based on 5) at 0 °C
for 3 h. a Data in square brackets are the results with the use of CCl3CO2H
(100 mol%) at 25 °C for 5 h. b Results after recrystallization. c 1 mol% of
(R)-3a was used.
Fortunately, more stable NCbz aldimine 4b in place of
less stable NCO2Me aldimine 4a could be used in a scalable
aza-FC reaction of 5a (2.2 mmol), and the corresponding
6m was obtained in 88% yield (0.66 g), although the enanti-
oselectivity was still moderate (63% ee).22 Treatment of 6m
with trifluoromethanesulfonic anhydride (Tf2O) gave 10,
which was used in Suzuki–Miyaura coupling with PhB(OH)2
to give 11 quantitatively. Recrystallization of 11 improved
the optical purity to 98% ee. Finally, after deprotection of
the NCbz moiety with the use of trimethylsilyl iodide, the
desired key compound 1226e was obtained in 92% yield.
To consider the reaction mechanism, particularly the
para-selectivity of phenols, several control experiments
were performed. When anisole (13), instead of unsubstitut-
ed phenol (5a), was used with 4a, the reaction did not pro-
ceed (Scheme 6a). This result suggests that the deprotona-
tion process of phenol might be necessary to promote the
reaction.
To demonstrate the synthetic utility of the present cata-
lytic system, we performed a formal total synthesis of (R)-
bifonazole, which is a well-established antifungal agent for
superficial mycoses (Scheme 5).26,27
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

F
H. Okamoto et al.
Feature
Synthesis
Moreover, the enantioselectivity of para-adduct 19 was low
(5% ee), and thus meta-substituted phenols would not be
suitable in the present reaction system, probably because
the para-addition reaction is preferred due to steric rea-
sons. Next, we examined whether or not 1-naphthol (21)
could be used for the para-selective reaction (Scheme 6d).
As a result, the reaction proceeded preferentially at the 2-
position (i.e., ortho-position) of 21, and compound 23 was
obtained in 43% yield with 24% ee. However, 4(para)-ad-
duct 22 was barely obtained in 14% yield with 11% ee, even
though 1-naphthol (21) is strongly conjugated between the
1- and 2-positions and the 2(ortho)-adduct would usually
be dominant.28 Although the enantioselectivity of 22 was
still low at this stage, para-addition-induced catalyst (R)-3a
might show some resistance such as in the normally ortho-
addition of 1-naphthol (21).
Cbz
Cbz
(R)-3a
(5 mol%)
HN
N
PhOH
+
Ph
Ph
H
CHCl3 (0.01 M)
5a
0 °C, 3 h
(2.2 mmol)
4b (1.5 equiv)
OH
6m, 88% (0.66 g), 63% ee
Pd(PPh3)4
PhB(OH)2
Cbz
HN
Cbz
HN
Tf2O, Et3N
CH2Cl2
r.t., 2 h
toluene
K2CO3
Ph
Ph
Ph
11, >99%
OTf
90 °C, 16 h
10, >99%
recrystallization
50% (0.40 g), 98% ee
N
NH2
Ph
N
ref. 26e
Me3SiI
CH2Cl2
r.t., 1 h
Ph
Ph
12, 92%, 98% ee
Ph
(R)-bifonazole
To elucidate the function of the Brønsted acid parts of
(R)-3a, (R)-24 was used as a catalyst, which was prepared
from (R)-3a by Me-protecting one of the P(=O)OH moieties
(Scheme 7). Catalyst (R)-24 was used as an inseparable di-
astereomeric mixture based on the chiral P center (dr =
76:24). As a result, the reaction of 5a with 4a proceeded,
and 6a (41% yield with 0% ee) and 7a (11% yield with 9% ee)
were obtained. Neither regio-selectivity nor enantioselec-
tivity was effectively induced. Therefore, the double
P(=O)OH moieties in (R)-3a should be essential for success-
ful activation of the aldimine and phenol.
Scheme 5 Transformation toward (R)-bifonazole
(a)
(R)-3a
CO2Me
CO2Me
OMe
HN
HN
(5 mol%)
+
+
4a
+
Ph
Ph
MeO
CHCl3 (0.1 M)
(1.5 equiv)
0 °C, 3 h
OMe
13
No reaction
14, 0%
CO2Me
15, 0%
(b)
OH
(R)-3a
HN
(5 mol%)
Me
4a
Ph
3,5-Ph2C6H3
O
CHCl3 (0.1 M)
(1.5 equiv)
0 °C, 3 h
HO
Me
O
OH
P
17, 8%, 0% ee
16
O
(c)
*
CO2Me
CO2Me
OH
P
OMe
HN
HN
(R)-3a
O
O
(5 mol%)
+
+
4a
Ph
Ph
3,5-Ph2C6H3
CO2Me
CO2Me
CHCl3 (0.1 M)
(1.5 equiv)
Me
HN
HN
HO
(R)-24 (P*-dr = 76:24)
Me
19, 3%, 5% ee
OH
HO
Me
0 °C, 3 h
(5 mol%)
+
4a
(1.5 equiv)
5a
18
20, 2%, 4% ee
+
Ph
Ph
CHCl3 (0.01 M)
0 °C, 3 h
(d)
OH
OH
6a
41%, 0% ee
7a
(R)-3a (5 mol%)
+
4a
11%, 9% ee
CHCl3 (0.01 M)
(1.5 equiv)
Scheme 7 Role of two P(=O)OH moieties of the catalysts
0 °C, 3 h
21
MeO2C
Ph
MeO2C
As expected in Scheme 2d, we considered an activation
model. To support the consideration that aldimine 4 and
phenol 5 might be activated independently by two acid-
base moieties of (R)-3a, preliminary competition experi-
ments were performed with either two different aldimines
or phenols (Scheme 8). If a more complicated activation
mechanism with the two acid-base moieties of (R)-3a is in-
volved, the enantioselectivity of the products might be af-
fected by the interaction among the competitive substrates.
First, we examined a reaction with the use of two different
aldimines 4a and 4c (Scheme 8a). As a result, the corre-
sponding products 6b and 6n were obtained with almost
the same enantioselectivities as in the case with each alone.
Next, a reaction with the use of two different phenols 5a
NH
NH OH
Ph
+
22
14%, 11% ee
23
43%, 24% ee
OH
Scheme 6 Control experiments with other phenols and naphthols
Moreover, when p-cresol (16) was used, the corre-
sponding ortho-adduct 17 was obtained in only 8% yield
with 0% ee (Scheme 6b). This result strongly suggests that
para-selective activation might occur in our reaction sys-
tem. Moreover, we also examined the reaction with m-
cresol (18) (Scheme 6c). As a result, both para-adduct 19
and ortho-adduct 20 were obtained in very low yields.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

G
H. Okamoto et al.
Feature
Synthesis
and 5b was examined (Scheme 8b). As a result, the corre-
sponding products 6a and 6b were obtained with almost
the same enantioselectivities as in the case with each alone.
R
H
O
MeO2C
N
H
H
O
si-face attack
(a)
OH
(R)-3a (5 mol%)
CO2Me
Boc
O
O
O
N
N
Me
P
P
+
+
OH
CHCl3 (0.1 M)
O
Ph
H
Ph
H
O
0 °C, 3 h
4a
4c
5b
(1 equiv)
CO2Me
Boc
HN
HN
(0.75 equiv) (0.75 equiv)
Me
+
Me
OH
Ph
Ph
OH
Figure 1 A possible transition state
6b, 54%, 73% ee
6n, 46%, 52% ee
as above
as above
+
5b
4a
6b, >99%, 70% ee
to 4a might proceed, and the corresponding (R)-isomer 6
might be provided with high regio-selectivity and moderate
to good enantioselectivities. Some ortho-substituted phe-
nols, which offered higher enantioselectivities than unsub-
stituted phenol (5a), might help to provide the favored
transition state, since the ortho-substituent would direct
outward, as shown in Figure 1. Moreover, an electrostatic
π–π stacking interaction between 4 and 5 cannot be ruled
out, where a not very bulky but electron-donating ortho-
substituent on phenol might be effective, as shown in
Scheme 4.
In summary, we have developed chiral BINOL-derived
pyrophosphoric acid catalysts for the first time, which were
effective for the para-selective and enantioselective aza-
Friedel–Crafts reaction of phenols to aldimines. Since phe-
nols have an ortho/para-orientation, exclusive para-addi-
tion is difficult and geometric remote control would be
needed through the use of designer chiral catalysts. With
the use of the present chiral pyrophosphoric acid catalysts,
both aldimines and phenols would be activated coopera-
tively, and phenols could react at a para-position with mod-
erate to good enantioselectivities. Moreover, transforma-
tion of a product into (R)-bifonazole was demonstrated on
an enlarged scale. This is the first example of chiral pyro-
phosphoric acid catalysts, and the further application to
asymmetric reactions is underway.
(1 equiv)
(1.5 equiv)
+
4c
5b
6n, 92%, 48% ee
(1 equiv)
(1.5 equiv)
(b)
Ph
OH
OH
CO2Me
Me
(R)-3a (5 mol%)
N
+
+
CHCl3 (0.1 M)
H
0 °C, 3 h
4a
5a
5b
CO2Me
CO2Me
(1.5 equiv) (0.5 equiv)
(0.5 equiv)
HN
HN
Me
OH
+
Ph
Ph
OH
6a, 85%, 52% ee
6b, >99%, 72% ee
as above
+
4a
5a
6a, 85%, 53% ee
(1.5 equiv)
(1 equiv)
as above
+
6b, >99%, 70% ee
4a
5b
(1.5 equiv)
(1 equiv)
Scheme 8 Control experiments with competitive substrates
Overall, a possible activation mechanism might involve
a (R)-3a:4:5 ratio of 1:1:1, as shown in Scheme 2d, and (R)-
3a·42·5, (R)-3a·4·52, (R)-3a·42·52, or more complicated spe-
cies might be unlikely.
Based on the above experimental results, Figure 1
shows a possible transition state through the use of (R)-
3a·4·5 as a working model. Due to the steric constraints of
bulky aryl substituents at the 3,3′-positions, each aldimine
4a and phenol 5 might be activated independently at two
different P(=O)OH sites of (R)-3a. Phenol 5 would be depro-
tonated by a Brønsted base moiety (P=O) at one site, where-
as aldimine 4a would coordinate to the Brønsted acid cen-
ter (POH) at the other site. To avoid significant steric con-
straint due to the catalyst, the aryl moiety of 4a might be
oriented inward.
1H NMR spectra were recorded on a JEOL ECS400 (400 MHz) spec-
trometer at ambient temperature, unless otherwise noted. Data were
recorded as follows: chemical shift in ppm from internal TMS on the δ
scale, multiplicity (standard abbreviations), coupling constant (Hz),
integration, and assignment. 13C NMR spectra were recorded on a
JEOL ECS400 (100 MHz) spectrometer. Chemical shifts were recorded
in ppm from the solvent resonance employed as the internal standard
(CDCl3 at 77.10 ppm). 19F NMR spectra were recorded on a JEOL ECS-
400 (376 MHz) spectrometer. Chemical shifts were recorded in ppm
from the solvent resonance employed as the external standard (CFCl3
at 0 ppm). 31P NMR spectra were recorded on a JEOL ECS-400 (161
MHz) spectrometer. Chemical shifts were recorded in ppm from the
solvent resonance employed as the external standard (H3PO4 at 0
ppm). High-resolution mass spectral analyses (HRMS) were per-
Thus, a para-selective reaction pathway might be suit-
able, since the para-position of 5 would be close to the imi-
no-carbon of 4a, while the ortho-position of 5 would be far
from the imino-carbon of 4a. As a result, si-face attack of 5
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

H
H. Okamoto et al.
Feature
Synthesis
formed at Chemical Instrument Center, Nagoya University (JEOL JMS-
700 (FAB), JEOL JMS-T100GCV (EI), Bruker Daltonics micrOTOF-QII
(ESI)). IR spectra were recorded on a JASCO FT/IR 460 plus spectrome-
ter. High-performance liquid chromatography (HPLC) analysis was
conducted using Shimadzu LC-10 AD coupled diode array-detector
SPD-M20A and chiral column of Daicel CHIRALCEL OD-H, OD-3 and
CHIRALPAK AS-3, IA-3, IC-3. Optical rotations were measured on Ru-
dolph Autopol IV digital polarimeter. X-ray analysis was performed by
Rigaku PILATUS-200K. The products were purified by column chro-
matography on silica gel (Kanto Chemical Co., Inc. 37560). In experi-
ments that required anhydrous solvents such as CHCl3 were distilled
in prior to use. Aldimines 4 were known compounds and were pre-
pared based on the literature procedure.29 Phenols are commercially
available, although 2-(trimethylsilyl)phenol was prepared from 2-
bromophenol based on the literature procedure.30
(R)-3,3-Di(4-biphenyl)-1,1′-binaphthyl-2,2′-pyrophosphoric Acid
[(R)-3c]
Pale yellow solid; yield: 7.3 mg (99%); [α]D30 +112.0 (c 1.00, THF).
IR (KBr): 3408, 3056, 2930, 1656, 1488, 1428, 1396, 1246, 1194, 1104,
cm–1
.
1H NMR (THF-d8, 400 MHz): δ = 7.13 (br, 2 H), 7.28–7.35 (m, 4 H),
7.37–7.52 (m, 6 H), 7.60–7.82 (m, 12 H), 8.01 (m, 2 H), 8.15 (s, 2 H)
(Two P–OH moieties were not clearly observed.).
13C NMR (THF-d8, 100 MHz): δ = 125.9 (2 C), 126.4 (2 C), 126.8 (2 C),
127.2 (4 C), 127.7 (4 C), 127.8 (2 C), 127.9 (2 C), 129.1 (2 C), 129.5 (4
C), 130.9 (4 C), 132.1 (2 C), 132.7 (2 C), 134.0 (2 C), 135.4 (2 C), 138.6
(2 C), 140.3 (2 C), 141.7 (2 C), 146.3 (2 C).
31P NMR (THF-d8, 160 MHz): δ = –20.2.
HRMS (ESI): m/z [M – H]– calcd for C44H29O7P2: 731.1383; found:
731.1380.
Chiral 1,1′-Binaphthyl-2,2′-pyrophosphoric Acids (R)-3; General
Procedure (Table 2)
Catalytic Enantioselective Aza-Friedel–Crafts Reaction of Phenols
5 with Aldimines 4; General Procedure (Scheme 4)
To a solution of chiral bis(phosphoric acid) (R)-27 (0.010 mmol) in
CH2Cl2 (0.2 mL) was added one drop of DMF. Oxalyl chloride (3.0 μL,
0.035 mmol) was added at r.t., and the reaction mixture was warmed
to 40 °C. The mixture was stirred at 40 °C for 5 min. After the mixture
was allowed to cool to r.t., toluene (2 mL) was added. The volatiles
were removed in vacuo, and the desired pyrophosphoric acid (R)-3
was obtained, which was used for the catalysis without further purifi-
cation. A small amount of DMF and CH2Cl2 were usually involved.
To a well-dried round-bottomed flask (50 mL) containing (R)-3a (8.8
mg, 0.010 mmol), which was prepared in situ in advance, were added
CHCl3 (18 mL) and aldimine 4 (0.30 mmol) under a N2 atmosphere.
The solution was cooled to 0 °C, and then a solution of phenol 5 (0.20
mmol) in CHCl3 (2 mL) was added. The resultant mixture was stirred
at 0 °C for 3 h. To quench the reaction, Et3N (0.20 mL, 1.44 mmol) was
added at 0 °C and the mixture was stirred for 5 min. Brine (10 mL)
was poured into the reaction mixture, and the product was extracted
with EtOAc (2 × 10 mL). The combined extracts were washed with
brine (10 mL) and dried (Na2SO4). The organic phase was concentrat-
ed under reduced pressure, and the resultant residue was purified by
silica gel column chromatography (eluent: n-hexane/EtOAc = 5:1 to
3:1) to give the desired product 6. Hydrolyzed catalyst (R)-2a [partial-
ly, some metal salts of (R)-2a] could be recovered through the same
silica gel column chromatography (eluent: CHCl3/MeOH = 3:1) almost
quantitatively. If the catalyst was to be reused for another reaction,
further purification with washing by aq 1 M HCl was necessary. The
enantiomeric purity of 6 was determined by HPLC analysis.
(R)-3,3′-Di(3,5-terphenyl)-1,1′-binaphthyl-2,2′-pyrophosphoric
Acid [(R)-3a]
Pale yellow solid; yield: 8.8 mg (99%), [α]D23 +60.0 (c 1.00, THF).
IR (KBr): 3444, 2929, 1655, 1498, 1402, 1239, 1191, 1088, 1029 cm–1
.
1H NMR (THF-d8, 400 MHz): δ = 4.00–5.00 (br, 2 H), 7.12 (d, J = 8.2 Hz,
2 H), 7.26–7.35 (m, 6 H), 7.37–7.50 (m, 10 H), 7.75–8.10 (m, 16 H),
8.31 (s, 2 H).
13C NMR (THF-d8, 100 MHz): δ = 125.6 (2 C), 126.0 (2 C), 126.3 (2 C),
126.8 (2 C), 127.9 (2 C), 128.0 (4 C), 128.2 (8 C), 128.3 (4 C), 129.1 (2
C), 129.5 (8 C), 132.5 (2 C), 132.7 (2 C), 134.2 (2 C), 135.4 (2 C), 140.5
(2 C), 142.3 (4 C), 142.5 (4 C), 146.5 (2 C).
Methyl (R)-[(4-Hydroxyphenyl)(phenyl)methyl]carbamate (6a)
Colorless oil; yield: 46.4 mg (90%); [α]D27 –16.0 (c 1.00, CHCl3, 63% ee).
31P NMR (THF-d8, 160 MHz): δ = –21.2.
HRMS (ESI): m/z [M – H]– calcd for C56H37O7P2: 883.2009; found:
IR (neat): 3326, 1698, 1508, 1456, 1362, 1233, 1038 cm–1
.
883.2008.
1H NMR (CDCl3, 400 MHz): δ = 3.69 (s, 3 H), 5.32 (br, 1 H), 5.74 (br,
1 H), 5.89 (br, 1 H), 6.73 (d, J = 8.7 Hz, 2 H), 7.05 (d, J = 7.3 Hz, 2 H),
7.20–7.28 (m, 3 H), 7.21–7.34 (t, J = 7.3 Hz, 2 H).
13C NMR (CDCl3, 100 MHz): δ = 52.6, 58.4, 115.6 (2 C), 127.2 (2 C),
127.5, 128.6 (2 C), 128.7 (2 C), 133.3, 141.8, 155.5, 156.7.
(R)-3,3′-Diphenyl-1,1′-binaphthyl-2,2′-pyrophosphoric Acid [(R)-
3b]
Pale yellow solid; yield: 5.8 mg (99%); [α]D26 +219.5 (c 1.00, THF).
IR (KBr): 3421, 3058, 1496, 1457, 1420, 1246, 1193, 993 cm–1
1H NMR (THF-d8, 400 MHz): δ = 6.60–7.20 (br, 2 H), 7.10 (d, J = 8.2 Hz,
2 H), 7.26–7.34 (m, 4 H), 7.38 (t, J = 7.3 Hz, 4 H), 7.46 (t, J = 7.3 Hz, 2
H), 7.67 (d, J = 7.3 Hz, 4 H), 8.00 (d, J = 8.2 Hz, 2 H), 8.10 (s, 2 H).
13C NMR (THF-d8, 100 MHz): δ = 125.9 (2 C), 126.2 (2 C), 126.8 (2 C),
127.7 (2 C), 127.8 (2 C), 128.7 (4 C), 129.1 (2 C), 130.4 (4 C), 132.2 (2
C), 132.7 (2 C), 133.9 (2 C), 135.8 (2 C), 139.4 (2 C), 146.3 (2 C).
.
HRMS (FAB): m/z [M + Na]+ calcd for C15H15NO3Na: 280.0950; found:
280.0944.
The enantiomeric purity of the product was determined by HPLC
analysis: Daicel CHIRALCEL OD-H, n-hexane/i-PrOH = 4:1, 210 nm,
flow rate = 0.6 mL/min, tR = 21.7 min (minor, S) and 25.9 min (major,
R).
31P NMR (THF-d8, 160 MHz): δ = –20.8.
HRMS (ESI): m/z [M – H]– calcd for C32H21O7P2: 579.0768; found:
Methyl [(2-Hydroxyphenyl)(phenyl)methyl]carbamate (7a)
Colorless oil; yield: 7.7 mg (15%, Table 1, entry 3).
IR (neat): 3407, 1696, 1600, 1519, 1457, 1348, 1267, 1025 cm–1
579.0757.
.
1H NMR (CDCl3, 400 MHz): δ = 3.72 (s, 3 H), 5.84 (br, 1 H), 6.17 (br,
1 H), 6.83–6.88 (m, 2 H), 6.99 (br, 1 H), 7.07 (br, 1 H), 7.15 (td, J = 7.8,
1.4 Hz, 1 H), 7.23–7.34 (m, 5 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

I
H. Okamoto et al.
Feature
Synthesis
13C NMR (CDCl3, 100 MHz): δ = 52.8, 54.8, 116.8, 120.4, 126.8 (2 C),
127.3, 128.5 (2 C), 128.8, 129.1 (2 C), 140.8, 154.2, 157.6.
IR (KBr): 3398, 3349, 1697, 1515, 1448, 1263, 1225, 1191, 1174, 1056
cm–1
.
HRMS (FAB): m/z [M + Na]+ calcd for C15H15NO3Na: 280.0950; found:
280.0942.
1H NMR (DMSO-d6, 400 MHz, 40 °C): δ = 3.56 (s, 3 H), 6.50 (d, J = 9.2
Hz, 1 H), 6.68 (d, J = 8.7 Hz, 2 H), 7.07 (d, J = 8.3 Hz, 2 H), 7.45 (t, J = 7.3
Hz, 1 H), 7.48–7.51 (m, 3 H), 7.84 (d, J = 7.8 Hz, 1 H), 7.93 (m, 1 H),
8.00 (m, 1 H), 8.13 (br, 1 H), 9.28 (br, 1 H).
13C NMR (DMSO-d6, 100 MHz, 40 °C): δ = 51.3, 54.2, 115.0 (2 C), 123.4,
124.3, 125.2, 125.4, 126.1, 127.4, 128.5, 128.7 (2 C), 130.4, 132.1,
133.3, 138.4, 155.9, 156.3.
The enantiomeric purity of the product was determined by HPLC
analysis: Daicel CHIRALCEL OD-H, n-hexane/i-PrOH = 4:1, 210 nm,
flow rate = 0.6 mL/min, tR = 10.9 min and 60.5 min.
Methyl (R)-[(4-Hydroxy-3-methylphenyl)(phenyl)methyl]carba-
mate (6b)
HRMS (ESI): m/z [M + Na]+ calcd for C19H17NO3Na: 330.1101; found:
330.1093.
21
Colorless solid; yield: 50.5 mg (93%); mp 119–123 °C; [α]D –23.6 (c
1.00, CHCl3, 82% ee).
IR (KBr): 3394, 2924, 1699, 1509, 1267, 1118, 1039 cm–1
1H NMR (CDCl3, 400 MHz): δ = 2.21 (s, 3 H), 3.69 (s, 3 H), 4.76 (s, 1 H),
5.25 (br, 1 H), 5.87 (br, 1 H), 6.70 (d, J = 8.2 Hz, 1 H), 6.92 (d, J = 8.2 Hz,
1 H), 6.99 (s, 1 H), 7.23–7.28 (m, 3 H), 7.32 (t, J = 6.9 Hz, 2 H).
13C NMR (CDCl3, 100 MHz): δ = 16.0, 52.5, 58.4, 115.0, 124.4, 125.9,
127.2 (2 C), 127.4, 128.6 (2 C), 129.9, 133.3, 142.0, 153.7, 156.6.
HRMS (FAB): m/z [M + Na]+ calcd for C16H17NO3Na: 294.1106; found:
294.1105.
The enantiomeric purity of the product was determined by HPLC
analysis: Daicel CHIRALCEL ID-3, n-hexane/i-PrOH = 4:1, 284 nm,
flow rate = 0.5 mL/min, tR = 24.4 min (major, S) and 29.3 min (minor,
R).
.
Methyl (R)-[(3-Allyl-4-hydroxyphenyl)(phenyl)methyl]carbamate
(6e)
Colorless oil; yield: 39.2 mg (66%); [α]D27 –29.9 (c 1.00, CHCl3, 76% ee).
IR (neat): 3326, 2923, 2855, 1698, 1267 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 3.36 (d, J = 6.4 Hz, 2 H), 3.69 (s, 3 H),
5.08–5.20 (m, 2 H), 5.30 (br, 1 H), 5.40 (br, 1 H), 5.89 (d, J = 7.3 Hz, 1
H), 5.96 (m, 1 H), 6.71 (d, J = 8.2 Hz, 1 H), 6.93 (d, J = 8.2 Hz, 1 H), 6.97
(s, 1 H), 7.22–7.27 (m, 3 H), 7.30–7.34 (m, 2 H).
13C NMR (CDCl3, 100 MHz): δ = 35.3, 52.5, 58.4, 116.0, 116.7, 125.7,
126.8, 127.2 (2 C), 127.5, 128.7 (2 C), 129.5, 134.0, 136.3, 142.0, 153.7,
156.4.
The enantiomeric purity of the product was determined by HPLC
analysis: Daicel CHIRALCEL OD-H, n-hexane/i-PrOH = 4:1, 254 nm,
flow rate = 0.6 mL/min, tR = 17.8 min (minor, S) and 25.9 min (major,
R).
Methyl [(2-Hydroxy-3-methylphenyl)(phenyl)methyl]carbamate
(7b)
HRMS (FAB): m/z [M + Na]+ calcd for C18H19NO3Na: 320.12657; found:
Colorless oil; yield: 9.5 mg (17%, Scheme 3b).
320.1257.
IR (neat): 3410, 1703, 1518, 1468, 1345, 1266, 1193, 1028 cm–1
.
The enantiomeric purity of the product was determined by HPLC
analysis: Daicel CHIRALCEL OD-H, n-hexane/i-PrOH = 4:1, 230 nm,
flow rate = 0.6 mL/min, tR = 13.3 min (minor, S) and 23.8 min (major,
R).
1H NMR (CDCl3, 400 MHz): δ = 2.26 (s, 3 H), 3.72 (s, 3 H), 5.72 (br, 1 H),
6.20 (d, J = 8.2 Hz, 1 H), 6.60 (br, 1 H), 6.78 (t, J = 7.8 Hz, 1 H), 6.86 (d,
J = 8.2 Hz, 1 H), 7.08 (d, J = 8.2 Hz, 1 H), 7.25–7.38 (m, 5 H).
13C NMR (CDCl3, 100 MHz): δ = 16.1, 52.8, 54.7, 120.6, 125.6, 126.8 (2
C), 126.9, 127.5, 128.3, 128.7 (2 C), 130.6, 140.7, 152.6, 157.7.
HRMS (FAB): m/z [M + Na]+ calcd for C16H17NO3Na: 294.1106; found:
294.1108.
Methyl (R)-[(4-Hydroxy-3-iodophenyl)(phenyl)methyl]carbamate
(6f)
Colorless oil; yield: 8.5 mg (11%); [α]D25 –10.3 (c 1.00, CHCl3, 26% ee).
IR (neat): 3305, 2919, 1691, 1268, 1225, 1040 cm–1
.
Methyl (R)-(4-Hydroxyphenyl)(p-tolyl)methylcarbamate (6c)
1H NMR (CDCl3, 400 MHz): δ = 3.70 (s, 3 H), 5.24 (br, 1 H), 5.42 (s, 1 H),
5.87 (br, 1 H), 6.91 (d, J = 8.7 Hz, 1 H), 7.10 (dd, J = 8.2, 1.8 Hz, 1 H),
7.21 (d, J = 6.9 Hz, 2 H), 7.27–7.38 (m, 3 H), 7.54 (d, J = 2.3 Hz, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 52.6, 57.7, 85.8, 115.1, 127.3 (2 C),
127.8, 128.9 (2 C), 129.2, 135.4, 137.0, 141.2, 154.4, 156.3.
25
Colorless solid; yield: 31.8 mg (58%); mp 133–137 °C; [α]D –5.1 (c
0.87, CHCl3, 77% ee).
IR (KBr): 3361, 1664, 1542, 1512, 1439, 1266, 1039 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 2.33 (s, 3 H), 3.69 (s, 3 H), 4.92 (s, 1 H),
5.22 (br, 1 H), 5.86 (br, 1 H), 6.76 (dt, J = 8.7, 2.7 Hz, 2 H) 7.07–7.15 (m,
6 H).
13C NMR (CDCl3, 100 MHz): δ = 21.2, 52.6, 58.2, 115.6 (2 C), 127.2
(2 C), 128.6 (2 C), 129.4 (2 C), 133.5, 137.3, 139.0, 155.4, 156.6.
HRMS (FAB): m/z [M + Na]+ calcd for C15H14INO3Na: 405.9916; found:
405.9906.
The enantiomeric purity of the product was determined by HPLC
analysis: Daicel CHIRALCEL OD-H, n-hexane/i-PrOH = 4:1, 210 nm,
flow rate = 0.6 mL/min, tR = 16.9 min (minor, S) and 46.8 min (major,
R).
HRMS (ESI): m/z [M + Na]+ calcd for C16H17NO3Na: 294.1101; found:
294.1105.
The enantiomeric purity of the product was determined by HPLC
analysis: Daicel CHIRALPAK IA-3, n-hexane/i-PrOH = 4:1, 210 nm,
flow rate = 1.0 mL/min, tR = 8.8 min (major, R) and 11.5 min (minor, S).
Methyl (R)-{[4-Hydroxy-3-(trimethylsilyl)phenyl](phenyl)meth-
yl}carbamate (6g)
Colorless oil; yield: 36.2 mg (55%); [α]D25 –22.8 (c 1.00, CHCl3, 60% ee).
Methyl (S)-[(4-Hydroxyphenyl)(naphthalen-1-yl)methyl]carba-
mate (6d)
IR (neat): 3335, 2953, 1699, 1508, 1405, 1243, 1074 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 0.26 (s, 9 H), 3.69 (s, 3 H), 5.19 (br, 1 H),
5.28 (br, 1 H), 5.90 (br, 1 H), 6.57 (d, J = 8.2 Hz, 1 H), 6.99 (br, 1 H), 7.20
(s, 1 H), 7.22–7.28 (m, 3 H), 7.32 (t, J = 7.8 Hz, 2 H).
26
Colorless solid; yield: 41.3 mg (67%); mp 208–222 °C; [α]D –26.8 (c
1.00, MeOH, 60% ee).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

J
H. Okamoto et al.
Feature
Synthesis
13C NMR (CDCl3, 100 MHz): δ = –1.0 (3 C), 52.5, 58.6, 114.6, 125.8,
Methyl (R)-[(4-Hydroxy-3-methylphenyl)(naphthalen-2-yl)meth-
127.1 (2 C), 127.4, 128.6 (2 C), 129.7, 133.0, 134.4, 142.0, 156.5, 160.2.
yl]carbamate (6k)
Colorless oil; yield: 47.7 mg (74%); [α]D25 –28.6 (c 1.00, CHCl3, 68% ee).
HRMS (FAB): m/z [M + Na]+ calcd for C18H23NO3SiNa: 352.1345; found:
IR (neat): 3330, 1696, 1508, 1265, 1114, 1040 cm–1
.
352.1335.
1H NMR (CDCl3, 400 MHz): δ = 2.18 (s, 3 H), 3.71 (s, 3 H), 5.22 (s, 1 H),
5.37 (br, 1 H), 6.03 (br, 1 H), 6.66 (d, J = 8.2 Hz, 1 H), 6.90 (d, J = 7.8 Hz,
1 H), 7.00 (s, 1 H), 7.31 (d, J = 8.7 Hz, 1 H), 7.43–7.52 (m, 2 H), 7.71 (s,
1 H), 7.75–7.83 (m, 3 H).
The enantiomeric purity of the product was determined by HPLC
analysis: Daicel CHIRALCEL OD-H, n-hexane/i-PrOH = 4:1, 210 nm,
flow rate = 0.6 mL/min, tR = 7.5 min (minor, S) and 10.0 min (major, R).
Methyl (R)-[(4-Hydroxy-3-methylphenyl)(p-tolyl)methyl]carba-
mate (6h)
Colorless oil; yield: 53.0 mg (93%); [α]D27 –8.0 (c 1.00, CHCl3, 67% ee).
13C NMR (CDCl3, 100 MHz): δ = 15.9, 52.5, 58.5, 115.1, 124.4, 125.5 (2
C), 126.0, 126.1, 126.3, 127.7, 128.1, 128.5, 130.2, 132.7, 133.3, 133.5,
139.4, 153.6, 156.5.
IR (neat): 3334, 2921, 1697, 1511, 1268, 1117, 1039 cm–1
.
HRMS (FAB): m/z [M + Na]+ calcd for C20H19NO3Na: 344.1263; found:
1H NMR (CDCl3, 400 MHz): δ = 2.20 (s, 3 H), 2.32 (s, 3 H), 3.68 (s, 3 H),
4.90 (br, 1 H), 5.23 (br, 1 H), 5.83 (br, 1 H), 6.68 (d, J = 8.2 Hz, 1 H), 6.91
(d, J = 7.8 Hz, 1 H), 6.98 (s, 1 H), 7.12 (s, 4 H).
13C NMR (CDCl3, 100 MHz): δ = 16.0, 21.1, 52.4, 58.2, 115.0, 124.3,
125.8, 127.1 (2 C), 129.3 (2 C), 129.9, 133.7, 137.1, 139.1, 153.5, 156.5.
344.1257.
The enantiomeric purity of the product was determined by HPLC
analysis: Daicel CHIRALCEL OD-H, n-hexane/i-PrOH = 4:1, 254 nm,
flow rate = 0.6 mL/min, tR = 20.2 min (major, R) and 29.3 min (minor,
S).
HRMS (FAB): m/z [M + Na]+ calcd for C17H19NO3Na: 308.1257; found:
308.1261.
Methyl (S)-[(4-Hydroxy-3-methylphenyl)(thiophen-2-yl)meth-
yl]carbamate (6l)
Colorless solid; yield: 44.5 mg (80%); mp 42–45 °C; [α]D25 –9.6 (c 1.00,
CHCl3, 49% ee).
The enantiomeric purity of the product was determined by HPLC
analysis: Daicel CHIRALCEL OD-H, n-hexane/i-PrOH = 4:1, 280 nm,
flow rate = 0.6 mL/min, tR = 16.3 min (major, R) and 19.8 min (minor,
S).
IR (KBr): 3398, 2918, 1509, 1256, 1118, 1044 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 2.23 (s, 3 H), 3.70 (s, 3 H), 5.02 (s, 1 H),
5.36 (br, 1 H), 6.06 (br, 1 H), 6.72 (d, J = 8.2 Hz, 1 H), 6.81 (dm, J = 3.7
Hz, 1 H), 6.93 (dd, J = 5.3, 3.7 Hz, 1 H), 7.02 (d, J = 8.2 Hz, 1 H), 7.08 (br,
1 H), 7.22 (dd, J = 5.3, 1.4 Hz, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 16.0, 52.5, 54.6, 115.1, 124.3, 125.2,
125.6, 125.7, 126.9, 129.7, 133.4, 146.5, 153.8, 156.2.
Methyl (R)-[(4-Bromophenyl)(4-hydroxy-3-methylphenyl)meth-
yl]carbamate (6i)
Colorless oil; yield: 70.0 mg (99%); [α]D23 –2.8 (c 1.00, CHCl3, 28% ee).
IR (neat): 3327, 2922, 1697, 1511, 1266, 1118, 1071, 1039, 1011 cm–1
1H NMR (CDCl3, 400 MHz): δ = 2.19 (s, 3 H), 3.69 (s, 3 H), 5.22 (m, 2 H),
5.80 (br, 1 H), 6.65 (d, J = 8.2 Hz, 1 H), 6.85 (d, J = 7.8 Hz, 1 H), 6.93 (s, 1
H), 7.12 (d, J = 8.2 Hz, 2 H), 7.44 (d, J = 8.7 Hz, 2 H).
.
HRMS (FAB): m/z [M + Na]+ calcd for C14H15NO3SNa: 300.0670; found:
300.0666.
13C NMR (CDCl3, 100 MHz): δ = 16.0, 52.6, 58.0, 115.1, 121.3, 124.6,
126.0, 128.8 (2 C), 130.0, 131.7 (2 C), 132.8, 141.1, 153.8, 156.5.
HRMS (FAB): m/z [M + Na]+ calcd for C16H16BrNO3Na: 372.0206;
found: 372.0197.
The enantiomeric purity of the product was determined by HPLC
analysis: Daicel CHIRALCEL OD-H, n-hexane/i-PrOH = 4:1, 230 nm,
flow rate = 0.6 mL/min, tR = 15.4 min (minor, R) and 18.6 min (major,
S).
The enantiomeric purity of the product was determined by HPLC
analysis: Daicel CHIRALPAK AS-3, n-hexane/i-PrOH = 3:1, 230 nm,
flow rate = 1.0 mL/min, tR = 9.8 min (minor, S) and 11.0 min (major, R).
Large Scale Synthesis of Benzyl (R)-[(4-Hydroxyphenyl)(phe-
nyl)methyl]carbamate (6m) (Scheme 5)
To a well-dried round-bottomed flask (500 mL) containing (R)-3a
(99.4 mg, 0.113 mmol), which was prepared in situ in advance, were
added CHCl3 (200 mL) and aldimine 4b (810 mg, 3.39 mmol) under a
N2 atmosphere. The solution was cooled to 0 °C, and then a solution
of phenol (5a; 213 mg, 2.26 mmol) in CHCl3 (23 mL) was added. The
resultant mixture was stirred at 0 °C for 3 h. To quench the reaction,
Et3N (0.20 mL, 1.44 mmol) was added at 0 °C and the mixture was
stirred for 5 min. Brine (100 mL) was poured into the mixture, and
the product was extracted with EtOAc (2 × 100 mL). The combined
extracts were washed with brine (100 mL) and dried (Na2SO4). The
organic phase was concentrated under reduced pressure, and the re-
sultant residue was purified by silica gel column chromatography
(eluent: n-hexane/EtOAc = 5:1 to 3:1) to give the desired product 6m
(663 mg, 88%) as a colorless oil. Hydrolyzed catalyst (R)-2a [partially,
some metal salts of (R)-2a] could be recovered through the same sili-
ca gel column chromatography (eluent: CHCl3/MeOH = 3:1) almost
quantitatively. The enantiomeric purity of 6m was determined by
HPLC analysis; colorless oil; yield: 663 mg (88%); [α]D27 –13.6 (c 1.00,
CHCl3, 63% ee).
Methyl (S)-[(4-Hydroxy-3-methylphenyl)(naphthalen-1-yl)meth-
yl]carbamate (6j)
Colorless oil; yield: 52.7 mg (82%); [α]D26 –7.6 (c 1.00, CHCl3, 77% ee).
IR (neat): 3335, 2975, 1698, 1508, 1260, 1118 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 2.19 (s, 3 H), 3.70 (s, 3 H), 4.86 (d,
J = 9.6 Hz, 1 H), 5.31 (d, J = 8.2 Hz, 1 H), 6.62 (br, 1 H), 6.68 (d, J = 8.2
Hz, 1 H), 6.93 (br, 1 H), 7.04 (s, 1 H), 7.33 (m, 1 H), 7.41–7.48 (m, 3 H),
7.80 (d, J = 8.2 Hz, 1 H), 7.87 (m, 1 H), 7.97 (br, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 16.0, 52.6, 55.3, 115.0, 123.8, 124.4,
124.9, 125.3, 125.8, 125.9, 126.5, 128.4, 128.8, 130.0, 131.0, 133.0,
134.0, 137.4, 153.6, 156.4.
HRMS (FAB): m/z [M + Na]+ calcd for C20H19NO3Na: 344.1263; found:
344.1263.
The enantiomeric purity of the product was determined by HPLC
analysis: Daicel CHIRALCEL OD-H, n-hexane/i-PrOH = 4:1, 230 nm,
flow rate = 0.6 mL/min, tR = 21.7 min (minor, R) and 32.0 min (major,
S).
IR (neat): 3321, 1696, 1661, 1517, 1356, 1297, 1265, 1237, 1041 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

K
H. Okamoto et al.
Feature
Synthesis
1H NMR (CDCl3, 400 MHz): δ = 5.11 (s, 2 H), 5.41 (br, 1 H) 5.80 (br, 1
H), 5.90 (br, 1 H), 6.66–6.72 (m, 2 H), 7.03 (d, J = 7.3 Hz, 2 H), 7.21–
7.34 (m, 10 H).
13C NMR (CDCl3, 100 MHz): δ = 58.5, 67.3, 115.6 (2 C), 127.2 (2 C),
127.5, 128.3/128.5/128.6 (9 C), 133.2, 136.1, 141.7, 155.5, 156.0.
HRMS (FAB): m/z [M + Na]+ calcd for C27H23NO2Na: 416.1626; found:
416.1626.
The enantiomeric purity of the product was determined by HPLC
analysis: Daicel CHIRALPAK AD-H, n-hexane/i-PrOH = 4:1, 280 nm,
flow rate = 1.0 mL/min, tR = 12.9 min (minor, S) and 14.7 min (major,
R).
HRMS (FAB): m/z [M + Na]+ calcd for C21H19NO3Na: 356.1263; found:
356.1261.
(R)-1,1′-Biphenyl-4-yl(phenyl)methanamine (12)
The enantiomeric purity of the product was determined by HPLC
analysis: Daicel CHIRALPAK IC-3, n-hexane/i-PrOH = 85:15, 230 nm,
flow rate = 1.0 mL/min, tR = 14.1 min (minor, S), 20.9 min (major, R).
To a solution of 11 (55.9 mg, 0.14 mmol) in CH2Cl2 (0.56 mL) was add-
ed trimethylsilyl iodide (74 μL, 0.52 mmol) at r.t. under a N2 atmo-
sphere. The mixture was stirred at r.t. for 1 h and then quenched with
MeOH (5 mL). Volatiles were removed in vacuo, and the resulting res-
idue was dissolved in 30% aq AcOH and washed with Et2O (5 mL). The
aqueous layer was then neutralized with 1 M aq NaOH, and extracted
with EtOAc (2 × 10 mL). The combined extracts were washed with
brine and dried (Na2SO4). The organic phase was concentrated under
reduced pressure to give 12 (33.4 mg, 92%) as a colorless solid. The
enantiomeric purity of 12 was determined by chiral HPLC analysis
(R)-4-({[(Benzyloxy)carbonyl]amino}(phenyl)methyl)phenyl Tri-
fluoromethanesulfonate (10)
To a solution of 6m (663 mg, 1.99 mmol, 62% ee) and Et3N (0.70 mL,
4.98 mmol) in CH2Cl2 (5 mL) was added trifluoromethanesulfonic an-
hydride (721 μL, 4.38 mmol) at 0 °C under a N2 atmosphere. The mix-
ture was stirred at r.t. for 2 h. The resulting mixture was diluted with
EtOAc (10 mL) and brine (10 mL). The product was extracted with
EtOAc (2 × 20 mL), the combined organic layers were washed with
brine and dried (Na2SO4). The organic phase was concentrated under
reduced pressure to give compound 10 (930 mg, >99%) as a colorless
solid. This crude product was used in the next step without further
26
(98% ee); yield: 33.4 mg (92%); mp 69–74 °C; [α]D +19.6 (c 1.00,
CHCl3, 98% ee) {Lit.31b [α]D22 +8.9 (c 2.45, CHCl3, 66% ee)}.
IR, 1H NMR, 13C NMR, and HRMS data were consistent with previously
reported values.31
26
purification; yield: 930 mg (>99%); mp 112–114 °C; [α]D +18.4 (c
1.00, CHCl3, 62% ee).
IR (KBr): 3378, 3027, 2922, 2850, 1598, 1487, 1448, 1417, 1213, 1147
cm–1
.
IR (KBr): 3315, 3033, 1696, 1499, 1424, 1140, 1040 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 1.80 (br, 2 H), 5.27 (s, 1 H), 7.23 (m,
1 H), 7.30–7.36 (m, 3 H), 7.39–7.50 (m, 6 H), 7.52–7.58 (m, 4 H).
13C NMR (CDCl3, 100 MHz): δ = 59.6, 127.0 (2 C), 127.1 (4 C), 127.2 (2
1H NMR (CDCl3, 400 MHz): δ = 5.11 (s, 2 H), 5.41 (br, 1 H), 6.00 (br,
1 H), 7.19–7.24 (m, 4 H), 7.28–7.37 (m, 10 H).
C), 127.3 (2 C), 128.6 (2 C), 128.8 (2 C), 140.0, 140.9, 144.7, 145.5.
HRMS (EI): m/z [M]+ calcd for C19H17N: 259.1361; found: 259.1369.
13C NMR (CDCl3, 100 MHz): δ = 58.3, 67.3, 118.7 (q, JC,F = 319 Hz),
121.5 (2 C), 127.4 (2 C), 128.1, 128.3 (3 C), 128.6 (2 C), 129.0 (2 C),
129.1 (2 C), 136.1, 140.6, 142.3, 148.7, 155.6.
19F NMR (CDCl3, 376 MHz): δ = –72.7.
HRMS (FAB): m/z [M + Na]+ calcd for C22H18F3NO5SNa: 488.0755;
The enantiomeric purity of the product was determined by HPLC
analysis: Daicel CHIRALCEL OD-H, n-hexane/i-PrOH/Et2NH = 10:1:0.1,
254 nm, flow rate = 1.0 mL/min, tR = 35.0 min (major, R) and 40.1 min
(minor, S) [Lit.31b HPLC analysis (66% ee): Daicel CHIRALCEL OD-H, n-
hexane/i-PrOH/Et2NH = 100:10:0.1, 254 nm, 1.0 mL/min, tR = 25.9
min (major, R) and 28.2 min (minor, S)].
found: 488.0755.
Benzyl (R)-[1,1′-Biphenyl-4-yl(phenyl)methyl]carbamate (11)
To a solution of compound 10 (containing impurities from the previ-
ous step, 1.99 mmol) in toluene (40 mL) were added phenylboronic
acid (388 mg, 3.2 mmol), K2CO3 (340 mg, 2.46 mmol), and Pd(PPh3)4
(236 mg, 0.20 mmol). The mixture was heated to 90 °C, and stirred at
that temperature for 16 h. The resulting mixture was diluted with
EtOAc (20 mL) and aq 1.0 M HCl. The product was extracted with EtOAc
(2 × 20 mL), the combined organic layers were washed with brine (20
mL), and dried (Na2SO4). The organic phase was concentrated under
reduced pressure, and the crude product was purified by silica gel col-
umn chromatography (eluent: n-hexane/EtOAc = 5:1 to 3:1) to give 11
(783 mg, >99%) as a colorless solid. Recrystallization from n-hex-
ane/Et2O improved the optical purity to 98% ee (400 mg, 50% recov-
ery). The enantiomeric purity of 11 was determined by HPLC analy-
sis; colorless solid; yield: 783 mg (>99%); mp 109–116 °C; [α]D25 –5.7
(c 1.00, CHCl3, 98% ee).
Methyl [(2-Hydroxy-5-methylphenyl)(phenyl)methyl]carbamate
(17)
Colorless solid; yield: 4.5 mg (8%); mp 148–152 °C.
IR (KBr): 3421, 3322, 2958, 1689, 1509, 1450, 1334, 1274, 1238, 1121,
1038 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 2.23 (s, 3 H), 3.71 (s, 3 H), 5.89 (br, 1 H),
6.11 (br, 1 H), 6.61 (br, 1 H), 6.73 (d, J = 8.2 Hz, 1 H), 6.89 (s, 1 H), 6.95
(dd, J = 8.0, 1.8 Hz, 1 H), 7.22–7.34 (m, 5 H).
13C NMR (CDCl3, 100 MHz): δ = 20.6, 52.7, 55.4, 116.5, 126.7 (2 C),
127.1, 127.4, 128.4 (2 C), 129.4 (2 C), 129.5, 141.2, 151.8, 157.5.
HRMS (ESI): m/z [M + Na]+ calcd for C16H17NO3Na: 294.1101; found:
294.1091.
The enantiomeric purity of the product was determined by HPLC
analysis: Daicel CHIRALCEL OD-3, n-hexane/i-PrOH = 9:1, 230 nm,
flow rate = 1.0 mL/min, tR = 12.2 min and 17.4 min.
IR (KBr): 3322, 3031, 1686, 1519, 1489, 1231, 1134, 1040 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 5.13 (s, 2 H), 5.43 (br, 1 H), 6.03 (br, 1
H), 7.25–7.40 (m, 13 H), 7.43 (t, J = 7.3 Hz, 2 H), 7.52–7.59 (m, 4 H).
13C NMR (CDCl3, 100 MHz): δ = 58.7, 67.0, 127.1 (2 C), 127.3 (2 C),
127.4 (4 C), 127.6, 127.7 (2 C), 128.2 (2 C), 128.5 (2 C), 128.7 (2 C),
128.8 (2 C), 136.3, 140.4, 140.6, 140.7, 141.6, 155.7.
Methyl [(4-Hydroxy-2-methylphenyl)(phenyl)methyl]carbamate
(19)
Colorless oil; yield: 1.6 mg (3%).
IR (neat): 3332, 2923, 1695, 1610, 1504, 1453, 1358, 1232, 1097, 1027
cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

L
H. Okamoto et al.
Feature
Synthesis
1H NMR (CDCl3, 400 MHz, 40 °C): δ = 2.24 (s, 3 H), 3.69 (s, 3 H), 5.04 (s,
1 H), 5.18 (br, 1 H), 6.06 (br, 1 H), 6.61 (d, J = 7.8 Hz, 1 H), 6.62 (s, 1 H),
6.95 (d, J = 7.8 Hz, 1 H), 7.19 (d, J = 7.3 Hz, 2 H), 7.25 (t, J = 7.3 Hz, 1 H),
7.31 (t, J = 7.2 Hz, 2 H).
13C NMR (CDCl3, 100 MHz): δ = 53.1, 53.2, 120.6, 122.5, 122.9, 125.7,
125.8, 126.2, 126.7, 126.8 (2 C), 127.5, 127.7, 128.8 (2 C), 134.2, 139.5,
150.8, 158.8.
HRMS (FAB): m/z [M + Na]+ calcd for C19H17NO3Na: 330.1101; found:
330.1107.
13C NMR (CDCl3, 100 MHz, 40 °C): δ = 19.6, 52.5, 55.4, 112.9, 117.7,
127.4 (2 C), 127.5, 128.2, 128.7 (2 C), 132.1, 138.0, 141.5, 155.0, 156.3.
HRMS (ESI): m/z [M + Na]+ calcd for C16H17NO3Na: 294.1101; found:
294.1100.
The enantiomeric purity of the product was determined by HPLC
analysis: Daicel CHIRALPAK IC-3, n-hexane/i-PrOH = 9:1, 230 nm,
flow rate = 1.0 mL/min, tR = 12.8 min (major) and 14.7 min (minor).
The enantiomeric purity of the product was determined by HPLC
analysis: Daicel CHIRALPAK IC-3, n-hexane/i-PrOH = 85:15, 210 nm,
flow rate = 0.4 mL/min, tR = 33.8 min (minor) and 37.4 min (major).
(R)-24
Following the general procedure for (R)-3, (R)-24 was prepared from
the methyl ester of (R)-2a (9.2 mg 0.010 mmol).7 (R)-24 was obtained
(9.0 mg, 99%) as P-diastereomers (76:24; pale yellow solid), which
were not separable from each other, and the diastereomeric mixture
was used for subsequent analysis and the reaction. A small amount of
toluene was used under azeotropic conditions, but a small amount of
DMF and CH2Cl2 were involved; pale yellow solid; yield: 9.0 mg (99%);
[α]D30 +112.0 (c 1.00, THF).
Methyl [(2-Hydroxy-4-methylphenyl)(phenyl)methyl]carbamate
(20)
Colorless oil; yield: 1.2 mg (2%).
IR (neat): 3319, 1694, 1618, 1516, 1452, 1421, 1347, 1291, 1232,
1120, 1028 cm–1
.
1H NMR (CDCl3, 400 MHz, 40 °C): δ = 2.28 (s, 3 H), 3.72 (s, 3 H), 5.76
(d, J = 9.2 Hz, 1 H), 6.14 (d, J = 8.2 Hz, 1 H), 6.54 (br, 1 H), 6.68 (d, J = 7.8
Hz, 1 H), 6.69 (s, 1 H), 6.89 (d, J = 7.8 Hz, 1 H), 7.26–7.28 (m, 3 H), 7.33
(t, J = 7.8 Hz, 2 H).
13C NMR (CDCl3, 100 MHz, 40 °C): δ = 21.1, 52.8, 54.9, 117.3, 121.1,
124.9, 126.8 (2 C), 127.1, 128.4 (2 C), 128.7, 139.1, 141.2, 154.1, 157.6.
IR (KBr): 3408, 3056, 2930, 1656, 1488, 1428, 1396, 1246, 1194, 1104,
cm–1
.
1H NMR (THF-d8, 400 MHz): δ = 3.22 (d, JH,P = 11.9 Hz), 7.06–7.27 (m),
7.28–7.65 (m), 7.74–8.16 (m), 8.32 (s), 8.35 (s). Many peaks were
overlapped, and two P-OH moieties were not clearly observed.
13C NMR (THF-d8, 100 MHz): δ = 56.3 (d, JC,P = 5.8 Hz), 125.5, 125.8,
125.9, 126.0, 127.2, 128.1, 128.2, 128.3, 128.4, 128.7, 128.9, 129.2,
129.5, 129.7, 132.6, 132.7, 132.8, 134.0, 134.1, 135.3, 135.4, 135.6,
138.4, 139.5, 140.2, 142.2 (d, JC,P = 6.7 Hz), 142.5 (d, JC,P = 5.8 Hz),
146.2 (d, JC,P = 8.6 Hz), 146.5 (d, JC,P = 10.5 Hz). Many peaks were over-
lapped.
HRMS (FAB): m/z [M + Na]+ calcd for C16H17NO3Na: 294.1106; found:
294.1116.
The enantiomeric purity of the product was determined by HPLC
analysis: Daicel CHIRALPAK IC-3, n-hexane/i-PrOH = 4:1, 230 nm,
flow rate = 0.4 mL/min, tR = 18.5 min (major), 23.8 min (minor).
31P NMR (CDCl3, 160 MHz): δ = –20.8 (d, J = 26.0 Hz, minor), –20.6 (d,
J = 25.8 Hz, major), –20.2 (d, J = 26.0 Hz, major), –19.7 (d, J = 25.9 Hz,
minor).
HRMS (ESI): m/z [M – H]– calcd for C57H39O7P2: 897.2177; found:
897.2169.
Methyl [(4-Hydroxynaphthalen-1-yl)(phenyl)methyl]carbamate
(22)
25
Colorless solid; Yield: 8.7 mg (14%); mp 212–222 °C; [α]D +5.9 (c
0,54, CHCl3, 11% ee).
IR (KBr): 3335, 2946, 1699, 1528, 1391, 1339, 1274, 1237, 1053 cm–1
.
1H NMR (DMSO-d6, 400 MHz): δ = 3.56 (s, 3 H), 6.48 (d, J = 9.2 Hz, 1
H), 6.79 (d, J = 8.2 Hz, 1 H), 7.05 (d, J = 7.8 Hz, 1 H), 7.24 (m, 1 H), 7.28–
7.34 (m, 4 H), 7.44 (t, J = 7.3 Hz, 1 H) 7.50 (t, J = 7.2 Hz, 1 H), 7.93 (d,
J = 8.7 Hz, 1 H), 8.18 (d, J = 7.8 Hz, 2 H), 10.1 (s, 1 H).
tert-Butyl (R)-[(4-Hydroxy-3-methylphenyl)(phenyl)methyl]car-
bamate (6n)
27
Colorless oil; yield: 57.6 mg (92%); [α]D = –13.6 (c 1.00, CHCl3, 48%
ee).
13C NMR (DMSO-d6, 100 MHz): δ = 51.3, 54.3, 107.0, 122.6, 123.2,
124.3, 124.8, 125.8, 126.5, 126.9, 127.5 (2 C), 128.1, 128.2 (2 C), 131.9,
142.5, 152.7, 156.1.
IR (neat): 3337, 2977, 1685, 1613, 1508, 1367, 1269, 1164, 1117 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 1.44 (s, 9 H), 2.18 (s, 3 H), 5.13 (br, 1 H),
5.24 (br, 1 H), 5.80 (br, 1 H), 6.65 (m, 1 H), 6.88 (d, J = 7.8 Hz, 1 H), 6.96
(s, 1 H), 7.21–7.27 (m, 3 H), 7.30 (t, J = 7.8 Hz, 2 H).
HRMS (ESI): m/z [M + Na]+ calcd for C19H17NO3Na: 330.1101; found:
330.1100.
13C NMR (CDCl3, 100 MHz): δ = 16.0, 28.5 (3 C), 58.0, 80.0, 115.0,
124.3, 125.8, 127.1 (2 C), 127.2, 128.6 (2 C), 129.9, 133.7, 142.5, 153.5,
155.2.
The enantiomeric purity of the product was determined by HPLC
analysis: Daicel CHIRALPAK IC-3, n-hexane/i-PrOH = 9:1, 240 nm,
flow rate = 1.0 mL/min, tR = 23.1 min (minor), 35.4 min (major).
HRMS (FAB): m/z [M + Na]+ calcd for C19H23NO3Na: 336.1570; found:
336.1566.
Methyl (R)-[(1-Hydroxynaphthalen-2-yl)(phenyl)methyl]carba-
The enantiomeric purity of the product was determined by HPLC
analysis: Daicel CHIRALCEL OD-H, n-hexane/i-PrOH = 4:1, 230 nm,
flow rate = 0.6 mL/min, tR = 25.1 min (minor, S) and 30.0 min (major,
R).
mate (23)
25
Colorless solid; yield: 26.6 mg (43%); mp 115–122 °C; [α]D –23.3 (c
0,98, CHCl3, 24% ee).
IR (KBr): 3313, 3058, 1695, 1511, 1356, 1244, 1189, 1081 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 3.72 (s, 3 H), 5.78 (br, 1 H), 6.49 (d,
J = 9.6 Hz, 1 H), 6.93 (d, J = 8.2 Hz, 1 H), 7.22–7.40 (m, 6 H), 7.45–7.51
(m, 2 H), 7.73 (d, J = 8.2 Hz, 1 H), 8.33 (d, J = 7.4 Hz, 1 H) 8.47 (br, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

M
H. Okamoto et al.
Feature
Synthesis
Funding Information
(e) Bandini, M.; Eichholzer, A. Angew. Chem. Int. Ed. 2009, 48,
9608. (f) Terrasson, V.; de Figueiredo, R. M.; Campagne, J. M. Eur.
J. Org. Chem. 2010, 2635. (g) Zeng, M.; You, S.-L. Synlett 2010,
1289.
This work was financially supported by JSPS KAKENHI Grant Num-
bers JP26288046, JP17H03054, and JP15H05810 in Precisely Designed
Catalysts with Customized Scaffolding.
)(
(10) Selected papers for ortho-selective catalytic asymmetric FC
reaction of phenols with α,β-unsaturated carbonyl compounds,
nitro olefins, α-keto esters, aldimines, isatins, CF3-ketimines,
etc. (a) Zhao, J.-L.; Liu, L.; Gu, C.-L.; Wang, D.; Chen, Y.-J. Tetrahe-
dron Lett. 2008, 49, 1476. (b) Lv, J.; Li, X.; Zhong, L.; Luo, S.;
Cheng, J.-P. Org. Lett. 2010, 12, 1096. (c) Hajra, S.; Sinha, D.
J. Org. Chem. 2011, 76, 7334. (d) Yoshida, M.; Nemoto, T.; Zhao,
Z.; Ishige, Y.; Hamada, Y. Tetrahedron: Asymmetry 2012, 23, 859.
(e) Suzuki, Y.; Nemoto, T.; Kakugawa, K.; Hamajima, A.;
Hamada, Y. Org. Lett. 2012, 14, 2350. (f) Li, G.-X.; Qu, J. Chem.
Commun. 2012, 48, 5518. (g) Xu, Q.-L.; Dai, L.-X.; You, S.-L. Org.
Lett. 2012, 14, 2579. (h) Bai, S.; Liu, X.; Wang, Z.; Cao, W.; Lin, L.;
Feng, X. Adv. Synth. Catal. 2012, 354, 2096. (i) Kaur, J.; Kumar, A.;
Chimni, S. S. RSC Adv. 2014, 4, 62367. (j) Zhao, Z.-L.; Xu, Q.-L.;
Gu, Q.; Wu, X.-Y.; You, S.-L. Org. Biomol. Chem. 2015, 13, 3086.
(k) Ren, H.; Wang, P.; Wang, L.; Tang, Y. Org. Lett. 2015, 17, 4886.
(l) Zhou, D.; Huang, Z.; Yu, X.; Wang, Y.; Li, J.; Wang, W.; Xie, H.
Org. Lett. 2015, 17, 5554. (m) Vetica, F.; Marcia de Figueiredo, R.;
Cupioli, E.; Gambacorta, A.; Loreto, M. A.; Miceli, M.; Gasperi, T.
Tetrahedron Lett. 2016, 57, 750. (n) Wang, Y.; Jiang, L.; Li, L.; Dai,
J.; Xiong, D.; Shao, Z. Angew. Chem. Int. Ed. 2016, 55, 15142.
(o) Shikora, J. M.; Chemler, S. R. Org. Lett. 2018, 20, 2133.
(11) Only few para-selective catalytic asymmetric FC reaction of
phenols has been reported: (a) Zhao, J.-L.; Liu, L.; Gu, C.-L.;
Wang, D.; Chen, Y.-J. Tetrahedron Lett. 2008, 49, 1476. (b) Shao,
L.; Hu, X.-P. Org. Biomol. Chem. 2017, 15, 9837.
(12) (a) Ralston, A. W.; Ingle, A.; McCorkle, M. R.; Bauer, S. T. J. Org.
Chem. 1940, 5, 645. (b) Ralston, A. W.; Ingle, A.; McCorkle, M. R.
J. Org. Chem. 1942, 7, 457. (c) Gore, P. H.; Smith, G. H.; Thorburn,
S. J. Chem. Soc. C. 1971, 650.
(13) (a) Betti, M. Gazz. Chim. Ital. 1900, 30II, 301. (b) Betti, M. Gazz.
Chim. Ital. 1900, 30II, 310. (c) Betti, M. Gazz. Chim. Ital. 1903,
33II, 1. See also see a review: (d) Cardellicchio, C.; Capozzi, M. A.
M.; Naso, F. Tetrahedron: Asymmetry 2010, 21, 507.
(14) Very recently, Shao reported a catalytic enantioselective aza-FC
reaction of phenols with aldimines with the use of chiral phos-
phoric acid catalysts. ortho-Adducts were selectively obtained
with high enantioselectivities. See ref. 10n.
(15) To determine whether or not overreaction/decomposition of 6a
and 7a would occur with the use of strong acids, we used either
isolated product 6a or 7a alone in the presence of p-TsOH. As a
result, overreaction/decomposition was observed in both cases,
and the same unknown compounds as were observed under the
standard reaction conditions (Table 1, entry 8) were obtained.
(16) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem. Int. Ed. 2005,
44, 7424.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610250.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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(19) Unfortunately, we have not yet been able to synthesize chiral
bis(phosphoric acid)s and thus the corresponding chiral pyro-
phosphoric acids with more bulky substituents (e.g., 2,4,6-i-
Pr3C6H2) due to the steric constraints. With this regard, we have
already discussed the synthetic difficulty of the bulky catalysts
in our previous manuscript (ref. 7b).
(20) A higher concentration (i.e., >0.1 M based on 5 in CHCl3) gave
much lower enantioselectivities, whereas a lower concentration
gave almost the same enantioselectivity as with the optimal
concentration (0.01 M). Moreover, the effect of the reaction
temperature (–40, –20, 0, and 25 °C) was also investigated. As a
result, 0 °C gave better results in terms of yield and enantiose-
lectivity than the other temperatures.
(21) CHCl3 provided a better yield and enantioselectivity than other
low-polarity solvents, such as CH2Cl2, 1,2-dichloroethane, tolu-
ene, and benzotrifluoride. In contrast, no reaction occurred
when polar solvents were used, such as Et2O, THF, propionitrile,
and nitroethane.
(22) Aldimines with other N-protecting groups, such as CO2t-Bu
(Boc), showed lower enantioselectivities (see Scheme 8). Rela-
tively stable N-CO2CH2Ph (Cbz) aldimines could be used, but
showed slightly lower yields with almost the same enantiose-
lectivities as less stable NCO2Me aldimines. Moreover, no reac-
tion occurred when NCO2CH2 (9-fluorenyl) (Fmoc), NSO2Ph,
NPh, and NBn aldimines were used.
(23) We performed the 31P NMR (CDCl3) analysis after the routine
workup with Et3N. As a result, (R)-3·(Et3N)n was observed as a
sole peak at –19.7 ppm, which strongly suggests that (R)-3a was
intact during the reaction [cf. 31P NMR (CDCl3) spectra; (R)-3a: δ
= –20.8; (R)-2a: δ = –0.4].
(24) Compounds 6b, 6c, and 6d were subjected to X-ray analysis. See
the Supporting Information for details.
(25) As shown in Table 2 and Scheme 3, the catalytic activity of (R)-
1a was lower than that of (R)-3a, and (R)-1a did not promote
the reactions of 5b (0.01 M CHCl3) effectively at 0 °C for 3 h. A
mixture of the corresponding adducts 6 and 7 was obtained in
<5% yield.
(26) Synthesis of bifonazole: (a) Corelli, F.; Summa, V.; Brogi, A.;
Monteagudo, E.; Botta, M. J. Org. Chem. 1995, 60, 2008. (b) Botta,
M.; Corelli, F.; Gasparrini, F.; Messina, F.; Mugnaini, C. J. Org.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N