SN2 Reaction of Diarylmethyl Anions at Secondary Alkyl and Cycloalkyl Carbons

Article abstract of DOI:10.1002/ejoc.201801596

The substitution reaction of the diethyl allylic and propargylic phosphates with Ar₂CH anions was applied to sec-alkyl phosphates to compare reactivity and stereoselectivity. However, the substitution took place on the ethyl carbon of the diethyl phosphate group. We then found that the diphenyl phosphate leaving group ((PhO)₂PO₂) was suited for the substitution at the sec-alkyl carbon. Enantioenriched diphenyl sec-alkyl phosphates with different substituents (Me, Et, iPr) on the vicinal position underwent the substitution reaction with almost complete inversion (>99% enantiospecificity). The substitution reactions of cyclohexyl phosphates possessing cis or trans substituents (Me and/or tBu) at the C4, C3, and C2 positions of the cyclohexane ring were also studied to observe the difference in reactivity among the cis and trans isomers. A transition-state model with the phosphate leaving group ((PhO)₂PO₂) in the axial position was proposed to explain the difference. This model was supported by computational calculation of the virtual substitution reaction of the structurally simpler “dimethyl” cyclohexyl phosphates (leaving group = (MeO)₂PO₂) with MeLi. Furthermore, the calculation unexpectedly indicated higher propensity of (PhO)₂PO₂ as a leaving reactivity than alkyl phosphate groups such as (MeO)₂PO₂ and (iPrO)₂PO₂.

Full text of DOI:10.1002/ejoc.201801596

A Journal of
Accepted Article
Title: SN2 Reaction of Diarylmethyl Anions at Secondary Alkyl and
Cycloalkyl Carbons
Authors: Riku Shinohara, Narihito Ogawa, Hidehisa Kawashima,
Kyohei Wada, Shun Saito, Takashi Yamazaki, and Yuichi
Kobayashi
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801596
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10.1002/ejoc.201801596
European Journal of Organic Chemistry
FULL PAPER
SN2 Reaction of Diarylmethyl Anions at Secondary Alkyl and
Cycloalkyl Carbons
Riku Shinohara,[a] Narihito Ogawa,[a] Hidehisa Kawashima,[a] Kyohei Wada,[a] Shun Saito,[a] Takashi
Yamazaki,[b] and Yuichi Kobayashi*[a]
substitution,[6] Pd or Ni-catalyzed arylation,[7] transition metal-free
allylic and propargylic substitutions of 1 and 3 by the current
authors [Scheme 1, Eqs. (1) and (2)],[8] and other reactions.[9]
Among these, the transition metal-free substitution[8] was
Abstract: The substitution reaction of the diethyl allylic and
demonstrated to be applicable to secondary allylic and
propargylic phosphates with Ar2CH anions was applied to sec-alkyl
propargylic substrates. The reactions proceeded with inversion of
phosphates to compare reactivity and stereoselectivity. However, the
the stereochemistry and with high regioselectivity. The Pd- and
substitution took place on the ethyl carbon of the diethyl phosphate
Ni-catalyzed substitutions mentioned above[6] are also applicable
group. We then found that the diphenyl phosphate leaving group
to sec-carbons, although the regioselectivity is dependent on the
structures of the π-allyl Pd intermediates. Because the reactions
((PhO)2PO2) was suited for the substitution at the sec-alkyl carbon.
Enantioenriched diphenyl sec-alkyl phosphates with different
were fast (usually within 15 min), we continued similar
substituents (Me, Et, iPr) on the vicinal position underwent the
investigations using phosphates 5 derived from sec-alkyl alcohols.
substitution reaction with almost complete inversion (>99%
In the literature, tri(prim-alkyl) phosphates have been shown to
enantiospecificity). The substitution reactions of cyclohexyl
undergo substitution with diarylmethyl anions,[2m] but the reactivity
phosphates possessing cis or trans substituents (Me and/or tBu) at
and stereochemistry of the reaction with sec-alkyl phosphates
the C4, C3, and C2 positions of the cyclohexane ring were also
remain unexplored. To address this issue, several acyclic sec-
alkyl phosphates were subjected to the substitution to find high
studied to observe the difference in reactivity among the cis and trans
isomers. A transition-state model with the phosphate leaving group
reactivity and stereochemical inversion [Eq. (3)]. The substitution
((PhO)2PO2) in the axial position was proposed to explain the
was then applied to substituted cyclohexyl and cyclopentyl
difference. This model was supported by computational calculation of
phosphates 7 to evaluate the difference in the reactivity of the
the virtual substitution reaction of the structurally simpler "dimethyl"
various stereoisomers [Eq. (4)]. Furthermore, the transition-state
cyclohexyl phosphates (leaving group = (MeO)2PO2) with MeLi.
energies for the model substitutions of substituted cyclohexyl
Furthermore, the calculation unexpectedly indicated higher propensity
phosphates with MeLi (in place of Ph2CHLi) were calculated to
of (PhO)2PO2 as a leaving reactivity than alkyl phosphate groups such
determine if the theoretical data support the observed reactivity.
as (MeO)2PO2 and (iPrO)2PO2.
Previous substitution using 1 and 3
Ar
Ar
OP(O)(OEt)2
OTBS
Ar2CH2/nBuLi
Introduction
(1)
(2)
OTBS
THF, –15 °C, 15–60 min
1
2
The diarylmethyl group (Ar2CH) in a molecule is a unique
substructure, the specific position of which endows a molecule
with signature properties. The specific biological activities of
natural and artificial diarylmethane derivatives are such
examples.[1] Diarylmethyl groups have been constructed via
several types of reactions, such as nucleophilic substitution of
halides (and pseudo halides),[2] electrophilic substitution of
diarylmethanol derivatives,[3] arylation at benzylic carbons,[4]
coupling at benzylic carbons,[5] Pd- or Ni-catalyzed allylic
Ar
C5H11
Ar
OP(O)(OEt)2
as above
C5H11
TMS
TMS
3
4
New substrates 5 and 7 for substitution
Ar
R1
Ar
OP(O)(OPh)2
Ar2CH2/nBuLi
(3)
(4)
R2
R1
R2
THF, –15 °C–0 °C, 15–30 min
6
5
[a]
[b]
Riku Shinohara, Naruhito Ogawa, Hidehisa Kawashima, Kyohei
Wada, Shun Saito, Prof. Dr. Yuichi Kobayashi
Department of Bioengineering
Tokyo Institute of Technology
Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501 (Japan)
E-mail: ykobayas@bio.titech.ac.jp
Ar
Ar
OP(O)(OPh)2
Ar2CH2/nBuLi
R
R
(CH2)
n
(CH2)
n
THF, –15 °C, 15 min~7 h
7 (n = 1, 2)
8 (n = 1, 2)
Prof. Dr. Takashi Yamazaki
Division of Applied Chemistry, Institute of Engineering
Tokyo University of Agriculture and Technology
2-24-16 Nakamachi, Koganei 184-8588 (Japan)
Scheme 1. Previous and present substitutions with Ar2CHLi.
Supporting information for this article is available on the WWW
under https://doi.org/xxxxxxx.
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10.1002/ejoc.201801596
European Journal of Organic Chemistry
FULL PAPER
Ar
Ar
Results and Discussion
OP(O)(OPh)2
Ar2CHLi[a,b]
R2
12a–d[a]
R1
R2
R1
13a–g[a]
The attempted substitution reaction of a racemic alkyl diethyl
phosphate 9a with PhCHLi (2.9 equiv), which was prepared from
Ph2CH2 and nBuLi at 0 °C–rt in THF, was completed in 15 min.
However, the major product was not the desired compound 10,
but the by-product 11 (Scheme 2), whereas no elimination
products (olefins) were detected. Reaction at the Et carbon was a
rather ordinary result based on the steric hindrance around the
carbon bearing the phosphate group, and thus, di-tert-butyl,
diphenyl, and other bulky alkyl phosphates were envisaged as
prospective candidates for the reaction. Among them, diphenyl
phosphate 9b was chosen because of the availability of
ClP(O)(OPh)2 at a low cost.[10] The substitution with PhCHLi (2.9
equiv) under similar conditions was swift and clean, and afforded
10 in 89% yield. The substitutions with 1.5 and 1.2 equivs of
PhCHLi gave 10 in comparable yields. The ensuring
computational study of a model substitution (vide infra) indicated
that the diphenyl phosphate exhibits higher leaving potency than
the dialkyl phosphate, and thus the selection of the diphenyl
phosphate group, (PhO)2PO2, based on the availability proved
serendipitous.
THF, –15 °C–0 °C, 15–30 min
O
Ph
R1
Ph
R2
R2
R1
13a, R1 = R2 = Me, 99%[c]
13b, R1 = R2 = Et, 99%
13c, R1 = R2 = iPr, 85%
13d, R1 = Me, R2 = tBu, 0%
13e, R1 = R2 = Me, 81%
13f, R1 = R2 = Et, 79%
13g, R1 = R2 = iPr, 20%[d]
Scheme 3. Examination of the substitution.
[a] R1, R2 of 12a–d: a, Me, Me; b, Et, Et; c, iPr, iPr; d, Me, tBu. [b] Substitutions
were examined with 3 equiv of Ph2CHLi unless otherwise noted. [c] 97% yield
with 1.5 equiv of Ph2CHLi. [d] Calculated from the mixture of 13g and Ph2CH2
based on 1H NMR ratios.
Ph2CH2 (3.3 equiv)
nBuLi (2.9–3.3 equiv)
Ph
R
Ph
OP(O)(OPh)2
OTBS
Ph
Ph
OP(O)(OR)2
Ph
OTBS
Ph2CHLi (2.9–1.2 equiv)
THF, –15 °C, 15 min
Ph
Ph
R
THF, –15~0 °C, 15–30 min
+
Et
Ph
15a, 89%, 97.3% ee, 99.8% es
15b, 92%, 96.1% ee, 99.9% es
15c, 94%, 96.2% ee, 99.9% es
14a, 97.5% ee
14b, 96.2% ee
14c, 96.3% ee
9a (R = Et)
9b (R = Ph)
10
11
9a + Ph2CHLi (2.9 equiv)
9b + Ph2CHLi (2.9 equiv)
9b + Ph2CHLi (1.5 equiv)
9b + Ph2CHLi (1.2 equiv)
8%
89%
86%
85%
89%
for 14 and 15: a, Me; b, Et; c, iPr
–
–
–
Scheme 4. Reactions using enantioenriched phosphates.[a,b]
[a] Enantiomeric excess (ee) of substrates and products were determined by
chiral HPLC analysis: 14a–c, as such; 15a–c, derived to alcohols 16a–c
es: enantiospecificity defined as
ee)x100/substrate(% ee)].
Scheme 2. Preliminary results of the reaction.[a,b]
(Scheme 5).
[b]
[product(%
[a] Equivalents of Ph2CHLi were prepared from Ph2CH2 (3.3, 1.8, or 1.5 equiv)
and nBuLi (2.9, 1.5, or 1.2 equiv), respectively. [b] Yields were calculated from
the isolated mixture of 10, 11, and/or Ph2CH2 based on 1H NMR ratios.
The above method was then applied to diphenyl phosphates
of secondary alcohols possessing Me, Et, iPr and tBu substituents
as R1 and R2. The substitutions of 12a with 3 and 1.5 equivs of
PhCHLi afforded 13a in high yields. Similarly, 12b and 12c gave
13b and 13c in good yields, respectively. However, the tBu
substituent on 12d (R1 = Me, R2 = tBu) prevented the reaction
from proceeding (Scheme 3). The substitution of 12a and 12b with
9H-xanthene proceeded well to afford 13e and 13f in good yields.
However, the substitution with 12c was sluggish, plausibly due to
a steric reason. Based on these results, substitutions presented
in following paragraphs were carried using rather enough quantity
of the reagents.
The substitution was then studied using enantioenriched
phosphates 14a–c (96–98% ee), which gave 15a–c in good yields
(Scheme 4). The enantiomeric ratios of the products were
determined by chiral HPLC analysis of the desilylated alcohols
16a–c (Scheme 5), and a high enantiospecificity (es)[11,12] of >99%
was obtained. As expected from Scheme 3, the tBu derivative (R
= tBu) did not afford the product.
same tR on
chiral HPLC
Ph
R
Ph
Ph
R
Ph
PPTS
OTBS
OH
MeOH, rt, 2–3 h
82–91% yields
16a–c
16a–c
15a–c
(96.1–97.3% ee) (94.0–95.7% ee)
1) Ph2CH2/nBuLi
0 °C, 20–30 min
H2
Pd/C
Ph
R
Ph
OP(O)(OEt)2
OTBS
OH
18a–c[a,b]
R
65–79%
2) TBAF, THF
or PPTS, MeOH
17a–c
(96.5–97.9% ee)
Ph
Ph
OH
+
R
regioisomer 19b,c
Scheme 5. Stereochemical correlation.
[a] 18/19: a, >99:1; b, 92:8; c, 43:57. [b] Yield: 18a, 79%; 18b, 73%; 18c, 31%.
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10.1002/ejoc.201801596
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1) H2, Pd/C
24f participated in the reaction sluggishly, but produced 25f
stereoselectively in 44% yield after 4 h. In contrast, the trans
isomer 24g showed high reactivity to give 25g within 15 min. 2-
Methylcyclohexyl phosphate 24h gave 25h as well, whereas the
trans isomer 24i remained unreacted under the given conditions
(–15 °C, 3 h) and at rt for 14 h.
14a
1) nBuLi, (CH2O)n
2) Red-Al
OH
2) ClP(O)(OPh)2
NMI
OH
43%
OTBS
3) TBSCl, imid.
56%
ClP(O)(OEt)2
NMI
21a
20
17a
87%
The cis and trans stereochemistries of the products were
unambiguously determined by coupling constants of the protons
in the 1H NMR spectra, as summarized in Figure S1 in the
Electronic Supplementary Information (ESI), whereas the
stereochemistry of the phosphates were determined by
comparing the 1H NMR spectral data with the literature data or
secured by preparing according to the literature methods as
presented in ESI.
1) H2, Pd/C[b]
2) TBSCl, imid.
14b,c
OH
O
3) ClP(O)(OPh)2
NMI
OTBS
(S,S)-Ru cat.[c]
42–62%
R
R
OTBS
iPrOH
23b,c
22b,c
60–62%
1) Red-Al
17b,c
2) ClP(O)(OEt)2
NMI
31–50%
Ph
Scheme 6. Preparation of 14a–c and 17a–c.[a]
Ph2CH2/nBuLi
OP(O)(OPh)2
*
*
Ph
[a] 22b, 23b: R = Et; 22c, 23c: R = iPr. [b] The TBS group was removed from
23b. [c] RuCl[(S,S)-TsDPEN](p-cymene).
R
R
THF, –15 °C, 15 min–7 h
25a–h
24a–i
Ph
Ph
The absolute configuration of 15a was confirmed by the
consistency of the retention time of 16a (Scheme 5) on the chiral
HPLC column with that derived from enantioenriched alcohol 20
via 17a and 18a of the known stereochemistry[8] (Schemes 5 and
6). The inversion of the configuration of diphenyl phosphate 14a
by Ph2CHLi was thus established. Similarly, 15b and 15c were
desilylated to alcohols 16b and 16c, and the retention times on
the chiral HPLC column were the same as those of 16b and 16c
synthesized from ketones 22b,c via the asymmetric transfer
hydrogenation[13] and the transition metal-free allylic substitution
of the derived diethyl phosphates 17b and 17c (Schemes 5 and
6). The absolute configurations of intermediates 18b,c formed
from 17b,c were assigned by analogy with that of 18a. Based on
the high es, single-electron transfer reaction[14] (SET) via radical
coupling was excluded.
OP(O)(OPh)2
15 min
24a
25a, 88%
Ph
OP(O)(OPh)2
Ph
R
R
15 min
R
R
24b, R = tBu
24c, R = Me
25b, R = tBu, 80%
25c, R = Me, 71%
Ph
Ph
OP(O)(OPh)2
7 h
3 h
24d, R = tBu
24e, R = Me
25d, R = tBu, 77%
25e, R = Me, 82%
The regioselectivity of the allylic substitution[8] was
substituent-dependent for the sterically more biased allylic
phosphates 17b,c than the reported phosphate 17a (Scheme 5,
footnote [a]). Consequently, the substitution reaction of alkyl
phosphates 14a–c (Scheme 4) was a better choice for the
synthesis of sec-alkyl substituted diphenylmethane derivatives,
as the substitution is independent of the regiochemistry.
Cyclohexyl phosphate 24a and substituted cyclohexyl
phosphates 24b–i were next chosen as substrates for the
substitution reaction with Ph2CHLi. The reaction of unsubstituted
24a proceeded at –15 °C and was completed within 15 min to
produce 25a in 88% yield (Scheme 7). The tBu substituent in the
cis isomer 24b did not interfere with the substitution to produce
the trans isomer 25b in 80% yield with high stereoselectivity. In
contrast, the substitution reaction of the trans isomer 24d was
sluggish, but afforded the cis product 25d stereospecifically in
77% yield after 7 h. The different reactivity between the cis and
trans isomers was also observed for 4-methylcyclohexyl
phosphates 24c and 24e, but the stereoselectivity and yields of
25c and 25e were independent of the reactivity. Among the
stereoisomers of 3-methylcyclohexyl phosphates, the cis isomer
Ph
Ph
OP(O)(OPh)2
4 h
24f
25f, 44%[a]
Ph
Ph
OP(O)(OPh)2
OP(O)(OPh)2
OP(O)(OPh)2
15 min
15 min
3 h
24g
25g, 98%
Ph
Ph
24h
24i
25h, 90%
Ph
Ph
25i
Scheme 7. Reactions of substituted cyclohexyl phosphates.
[a] 24f was recovered in 27% yield.
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10.1002/ejoc.201801596
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OTBDPS
Ph2CH2/nBuLi
OTBDPS
H
The substituted cyclohexyl phosphates in Scheme 7 were
divided into two groups by reactivity: The highly reactive group
involves phosphates 24b, 24c, 24g, and 24h, whereas 24d, 24e,
24f, and 24i are among the slowly or marginally reactive
phosphate groups. The difference in the reactivity could be
explained in terms of the transition state (TS) model 26 depicted
in Scheme 8, in which the (PhO)2PO2 group occupies the axial
position to facilitate substitution with the Ph2CH anion. In the
stable chair conformations of phosphates 24b,c,g,h with the
equatorial substituent (tBu or Me), the leaving group is located in
the axial position, and the conformations would be transformed
into the TSs without conformational change. On the other hand,
both the substituent and leaving group in 24d,e,f,i reside in
equatorial positions in the chair conformations, and hence flipping
the conformations of 24e,f,i or changing the conformation of 24d
to the twist-boat for the substitution would result in an increase in
the overall activation energies. Furthermore, the steric interaction
between the axial Me and the Ph2CH anion would be most
significant for the 2-methyl substrate 24i, and the influence was
indeed reflected in the marginal reaction rate. To support the
above hypothesis, virtual substitution of the dimethyl phosphates
with MeLi was subjected to computational calculation of the Gibbs
free energies, and the results are presented in the latter
paragraph.
H
THF, –15 °C
H
H
H
H
Ph
O
15 min
80%
H
H
Ph
P(O)(OPh)2
28
27
OTBDPS
OTBDPS
H
H
as above
4 h
H
H
H
H
Ph
O
H
H
Ph
P(O)(OPh)2
29
30
Ph
as above
Ph
OP(O)(OPh)2
OP(O)(OPh)2
Ph
Ph
15 min
31
32, 84%
Ph
as above
15 min
Ph
Ph
Ph
34, 90%
33
Scheme 9. Reactions of other cycloalkyl phosphates.
To rationalize the difference in the reactivity of the cis and
trans isomers of the substituted cyclohexyl phosphates, virtual
substitution of phosphates 35 with MeLi producing 36 via
transition states (TS) 37 (Scheme 10, (A)) was subjected to
energy calculation using density functional theory (DFT).[15] The
calculations of the Gibbs free energies for the substitution were
performed by using the Gaussian 09W program,[16] at the
B3LYP/6-31+G* level of theory with the temperature parameter of
–15 °C (258 K), at which the real substitution summarized in
Scheme 7 took place.
PhO OPh
O
OP(OPh)2
P
O
O
CHPh2
25
Li
CH
Ph Ph
24
TS (26)
Scheme 8. Proposed stereochemical course of the reaction.
Substitution of the steroidal phosphate 27 with Ph2CLi gave
28, whereas substitution of stereoisomer 29 did not proceed
(Scheme 9). These results are attributed to the impracticality of
flipping of the steroidal ring system and changing to the twist-boat.
In contrast with the cyclohexyl phosphates, the cyclopentyl
stereoisomers 31 and 33 showed the normal reactivity (–15 °C
and 15 min for completion of the reactions), and produced 32 and
34 stereoselectively in good yields. The similar reactivity of 31 and
33 is attributed to a rapid equilibrium between the conformers
through low-energy barriers, which allows quick access to the
required conformer for the reaction.
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FULL PAPER
(A) reaction scheme
and 35i with MeLi were not consistent with the actual reactivity
order for 24d, 24f, and 24i with Ph2CHLi. A likely reason is that
Ph2CHLi is bigger than MeLi, and hence, the interaction between
Ph2CHLi and the axial Me group in the TS from 24i is more
significant than that between MeLi and the Me group in the model
TS 37i (Scheme S3, diagram G).
O
MeO OMe
OP(OMe)2
Me
P
MeLi
O
O
Li
R
R
R
C
H2
35
36
37
OMe
MeO
O
(B) conformations and transition states
diagram A
P
13.16
TS
O
Li
H
35–37b,d : in Scheme 11
35–37f,g,h,i :
tBu
Me
37b
O
O
Me
OP(OMe)2
Me
O
Me
O
Me
OP(OMe)2
OP(OMe)2
OP(OMe)2
0.00
O
H
tBu
35b
OP(OMe)2
35g
35f
Me
Li
35i
35h
Me
tBu
+
MeLi
36b
–80.27
O
Me
O
P
MeO
+
O
O
O
O
Me
P
Me
Me
OMe
Me
P
Me
O
O
O
Me
O
Me
P
Me
Li
diagram B
Li
O
Li
Me
Li
tBu
Me
O
O
O
O
Me
37h
Me
P
Li
Me
H
O
17.33
TS
O
37f
O
Me
O
37i
O
37g
P
Me
tBu
MeO
OMe
+
MeLi
5.77
H
twist-boat-37d
OP(OMe)2
O
twist-boat-35d
Scheme 10. Virtual substitution of phosphates 35 with MeLi.
O
O
Li
O
tBu
OP(OMe)2
P
MeO
+
O
tBu
Me
twist-boat-36d
0.00
35d
OMe
The energy changes calculated for the substitution of the
stable conformations of the cis and trans 4-tBu-cyclohexyl
phosphates 35b and 35d with MeLi are presented in Scheme 11
and Scheme S1 in the ESI. For 35d, twist-boat and unlikely chair
confomations were subjected to the calculation to determine
lower energy states for the former. The energy changes for 35f–i
are provided in the ESI (Schemes S2 and S3). For comparison,
the calculated TS energies are summarized in Table 1. The TS
energies of 37b and the products (36b and (MeO)2PO2Li) were
13.16 kcal/mol and –80.27 kcal/mol, respectively. The latter
energy was below the energy sum of the reactants (35b and MeLi)
and thus indicated the substitution to be exothermic (Scheme 11,
diagram A). In contrast, the activation energy for changing the
most stable conformation 35d (trans isomer) to twist-boat-35d
with axial (MeO)2PO2 and equatorial tBu was determined to be
5.77 kcal/mol, and hence the energy of TS, i.e., twist-boat-37d,
was raised to 17.33 kcal/mol (diagram B). The products directly
derived from this TS were twist-boat-36d and (MeO)2PO2Li, but
the energy level was lower than that of the reactants (35d + MeLi).
Furthermore, the conformation of twist-boat-36d was changed to
the more stable chair conformation 36d. These energy levels of
TSs 37b and twist-boat-37d (Table 1, entries 1 and 2) are in good
agreement with the observed reactivity of the cis and trans
isomers 24b,d with Ph2CHLi (Scheme 7). The energy changes for
35f and 35g along the reaction coordinate were then calculated,
as depicted in Scheme S2 in the ESI. The TS energies (also
summarized in Table 1, entries 4 and 5) could account for the
observed reactivity of 24f and 24g. Similarly, the TS energies for
37h and 37i were determined (Scheme S3; Table 1, entries 6 and
7), and the difference in the energies supported the reactivity of
24h vs. 24i. In contrast to the TS energy difference between the
cis and trans isomers, the order of the TS energies for 35d, 35f,
Me
36d
Li
+
MeLi
–73.36
tBu
–76.95
+
P
MeO
O
OMe
Scheme 11. Virtual substitution of model phosphates 35b and 35d with MeLi
(diagrams A and B) at 258 K (–15 °C).[a,b]
[a] Computation was carried out by using Gaussian 09W (rev. D01) with the
B3LYP/6-31+G* level of theory. [b] Similar substitutions of 35f–i are shown in
diagrams C–F in the ESI.
Table 1. Transition state energies (ΔG≠) at 258K (–15 °C).
Entry
Phosphate
cis or trans
TS
TS energy[a]
1
2
3
4
5
6
7
35b
35d
35d
35f
cis
37b
13.16
17.33
19.56
14.12
10.97
10.28
15.51
trans
trans
cis
twist-boat-37d
flipped chair-37d
flipped chair-37f
37g
35g
35h
35i
trans
cis
37h
trans
flipped chair-37i
[a] kcal/mol.
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10.1002/ejoc.201801596
European Journal of Organic Chemistry
FULL PAPER
with EtOAc several times. The combined extracts were washed with brine,
dried over MgSO4 and concentrated under reduced pressure. The residual
oil was purified by chromatography on silica gel to give the phosphate.
Moreover, the TS energies (kcal/mol) calculated for the virtual
substitution of Me-OP(O)(OR)2 with MeLi producing Me-Me was
found to be dependent on the R group in the phosphates in the
following order: Ph, 0.83; Me, 1.7; iPr, 2.0, indicating that the
diphenyl phosphate group, (PhO)2PO2, is the most reactive
leaving group, though the prime reason for the use of this leaving
group was expectation of the clean substitution at the secondary
alkyl carbon.
Diphenyl (4-phenylbutan-2-yl) phosphate (9b): To a solution of 3-
phenylpropanal (0.200 mL, 1.52 mmol) in THF (5 mL) was add a solution
of MeLi (1.16 M in Et2O, 1.57 mL, 1.82 mmol) dropwise at –78 °C. After
the addition, the reaction temperature was allowed to slowly raise to rt and
stirred overnight. Saturated NH4Cl was added to the solution and the
resulting mixture was extracted with EtOAc twice. The combined extracts
were dried over MgSO4 and concentrated to afford 4-phenylbutan-2-ol,
which was passed through a short column of silica gel for the next reaction.
According to the general procedure for the phosphorylation of an alcohol,
a mixture of the above alcohol, diphenyl chlorophosphate (0.314 mL, 1.52
mmol), and N-methylimidazole (0.144 mL, 1.83 mmol) in CH2Cl2 (3 mL)
was stirred at rt for 12 h to afford phosphate 9b (439 mg, 75% yield over
two steps): liquid; Rf 0.45 (hexane/EtOAc 2:1); IR (neat) 1591, 1490, 1192,
Conclusions
The diphenyl phosphate group ((PhO)2PO2) was found to be a
good leaving group for the substitution of sec-alkyl diphenyl
phosphates with Ar2CH anions. Preliminary substitutions of iPr-,
Et2CH-, and (iPr)2CH-phosphates with Ph2CHLi and (9H-
xanthenyl)Li demonstrated that the substitutions took place
smoothly to afford iPr-CHAr2, Et2CH-CHAr2, and (iPr)2CH-CHAr2,
respectively. The study using enantioenriched sec-alkyl
phosphates indicated almost complete inversion (>99% es).
Cyclohexyl phosphates possessing cis or trans substituents (Me,
tBu) at the C4, C3, and C2 positions of the cyclohexane ring were
also subjected to the substitution to evaluate the difference in the
reactivity of the cis and trans isomers. To explain the difference,
a transition state model was proposed, in which the phosphate
leaving group ((PhO)2PO2) occupies the axial position to facilitate
the substitution. Furthermore, the Gibbs free energies of the
transition states in the virtual substitutions of structurally simpler
dimethyl phosphates (leaving group = (MeO)2PO2) with MeLi were
consistent with the reactivities of the real substitutions.
Furthermore, the calculation unexpectedly indicated that
(PhO)2PO2 exhibited higher leaving propensity than alkyl
phosphate groups such as (MeO)2PO2 and (iPrO)2PO2.
1012, 953 cm–1 1H NMR (400 MHz, CDCl3) δ 1.40 (d, J = 6.4 Hz, 3 H),
;
1.81–2.06 (m, 2 H), 2.56–2.72 (m, 2 H), 4.71–4.82 (m, 1 H), 7.08–7.38 (m,
15 H); 13C–APT NMR (100 MHz, CDCl3) δ 21.7, 31.3 (–), 39.1 (–) (d, J = 7
Hz), 77.8 (+) (m), 120.2, 125.4 (+), 126.1 (+), 128.4 (+), 128.5 (+), 129.9
(+), 141.2 (–), 150.8 (–) (d, J = 6 Hz); HRMS (EI+): m/z calcd for C22H23O4P
[M+] 382.1334, found 382.1327.
Diethyl (4-phenylbutan-2-yl) phosphate (9a): According to the general
procedure for the phosphorylation of an alcohol,
a mixture of 4-
phenylbutan-2-ol (172 mg, 1.15 mmol), diethyl chlorophosphate (0.20 mL,
1.39 mmol), and N-methylimidazole (0.14 mL, 1.78 mmol) in CH2Cl2 (5 mL)
was stirred at rt for 2 h to afford phosphate 9a (234 mg, 72% yield): liquid;
Rf 0.22 (hexane/EtOAc 2:1); IR (neat) 1261, 1031, 1003 cm–1 1H NMR
;
(400 MHz, CDCl3) δ 1.34 (dt, J = 0.8, 7.2 Hz, 6 H), 1.38 (d, J = 6.4 Hz, 3
H), 1.79–1.90 (m, 1 H), 1.93–2.04 (m, 1 H), 2.67 (ddd, J = 13.6, 10.0, 6.0
Hz, 1 H), 2.76 (ddd, J = 13.6, 10.0, 5.6 Hz, 1 H), 4.07–4.16 (m, 4 H), 4.48–
4.59 (m, 1 H), 7.16–7.31 (m, 5 H); 13C–APT NMR (100 MHz, CDCl3) δ 16.1
(+) (d, J = 7 Hz), 16.2 (+) (J = 7 Hz), 21.6 (+) (J = 3 Hz), 31.5 (–), 39.2 (–)
(J = 6 Hz), 63.5 (–) (d, J = 5 Hz), 63.6 (–) (d, J = 5 Hz), 75.4 (+) (d, J = 6
Hz), 125.9 (+), 128.3 (+), 128.4 (+), 141.5 (–); HRMS (FAB+): m/z calcd for
C14H24O4P [(M+H)+] 287.1412, found 287.1420.
Isopropyl diphenyl phosphate (12a): According to the general
procedure for the phosphorylation of an alcohol, a mixture of isopropanol
(0.080 mL, 0.97 mmol), diphenyl chlorophosphate (0.20 mL, 0.97 mmol),
and N-methylimidazole (0.084 mL, 1.07 mmol) in CH2Cl2 (2 mL) was stirred
at rt for 12 h to afford phosphate 12a (259 mg, 91% yield): liquid; Rf 0.70
(hexane/EtOAc 1:1); 1H NMR (400 MHz, CDCl3) δ 1.37 (dd, J = 6.0, 0.6
Hz, 6 H), 4.89 (d of sept., J = 7.2, 6.0 Hz, 1 H), 7.17 (t, J = 7.2 Hz, 2 H),
7.23 (d, J = 7.2 Hz, 4 H), 7.33 (t, J = 7.2 Hz, 4 H); 13C–APT NMR (100
MHz, CDCl3) δ 23.5 (+) (d, J = 6 Hz), 74.9 (+) (m), 120.1 (+) (d, J = 5 Hz),
125.2, 129.7 (+), 150.7 (–) (d, J = 7 Hz). The 1H and 13C NMR spectra were
consistent with those reported.[17]
Experimental Section
1. General Information: The 1H (300 or 400 MHz) and 13C NMR (75 or
100 MHz) spectroscopic data were recorded in CDCl3 using Me4Si (δ = 0
ppm) and the centerline of the triplet (δ = 77.1 ppm), respectively, as
internal standards. Signal patterns are indicated as br s (broad singlet), s
(singlet), d (doublet), t (triplet), q (quartet), and m (multiplet). Coupling
constants (J) are given in Hertz (Hz). Results of the attached proton test
(APT) in the 13C NMR experiments are given behind chemical shifts with
minus (for C and CH2) and plus (for CH and CH3) signs. High-resolution
mass spectroscopy (HRMS) was performed with a double-focusing mass
spectrometer with an ionization mode of positive FAB or EI as indicated
for each compound. The solvents that were distilled prior to use are THF
(from Na/benzophenone), Et2O (from Na/benzophenone), and CH2Cl2
(from CaH2). Products were purified by chromatography on silica gel
(Kanto, spherical silica gel 60N). (S)-3-Butyn-2-ol (20) was purchased from
Aldrich.
Pentan-3-yl diphenyl phosphate (12b): According to the general
procedure for the phosphorylation of an alcohol, a mixture of pentan-3-ol
(88 mg, 1.00 mmol), diphenyl chlorophosphate (0.21 mL, 1.02 mmol), and
N-methylimidazole (0.087 mL, 1.10 mmol) in CH2Cl2 (1 mL) was stirred at
rt for 11 h to afford phosphate 12b (271 mg, 85% yield): liquid; Rf 0.72
(hexane/EtOAc 1:1); IR (neat) 1738, 1591, 1490, 1193, 1012, 951 cm–1
;
1H NMR (400 MHz, CDCl3) δ 0.91 (t, J = 7.4 Hz, 6 H), 1.69 (quint., J = 7.4
Hz, 4 H), 4.54 (d of quint., J = 7.4, 6.0 Hz, 1 H), 7.17 (t, J = 7.2 Hz, 2 H),
7.23 (d, J = 7.2 Hz, 4 H), 7.33 (t, J = 7.2 Hz, 4 H); 13C–APT NMR (100
MHz, CDCl3) δ 9.1 (+), 27.2 (–) (d, J = 5 Hz), 84.4 (+) (d, J = 6 Hz), 120.1
(+) (d, J = 5 Hz), 125.1 (+), 129.7 (+), 150.8 (–) (d, J = 8 Hz); HRMS (EI+):
m/z calcd for C17H21O4P [M+] 320.1177, found 320.1172.
2. Synthesis of phosphates
General procedure for the phosphorylation of an alcohol: To a solution
of an alcohol (1 equiv) and N-methylimidazole (>1 equiv) in CH2Cl2 was
added diethyl chlorophosphate (>1 equiv). The solution was stirred at rt
and diluted with saturated NaHCO3. The resulting mixture was extracted
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10.1002/ejoc.201801596
European Journal of Organic Chemistry
FULL PAPER
2,4-Dimethylpentan-3-yl diphenyl phosphate (12c): According to the
general procedure for the phosphorylation of an alcohol, a mixture of 2,4-
dimethylpentan-3-ol (310 mg, 2.67 mmol), diphenyl chlorophosphate (0.55
mL, 2.66 mmol), and N-methylimidazole (0.23 mL, 2.92 mmol) in CH2Cl2
(2 mL) was stirred at rt for 12 h to afford phosphate 12c (832 mg, 89%
yield): liquid; Rf 0.58 (hexane/EtOAc 2:1); IR (neat) 1592, 1283, 1193,
1013, 944 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.97 (dd, J = 6.8, 2.0 Hz, 6
H), 1.99 (d of septet., J = 6.8, 5.6 Hz, 2 H), 4.30 (dt, J = 8.4, 5.6 Hz, 1 H),
7.14 (t, J = 7.6 Hz, 2 H), 7.21 (d, J = 7.6 Hz, 4 H), 7.30 (t, J = 7.6 Hz, 4 H);
13C–APT NMR (100 MHz, CDCl3) δ 17.1 (+), 19.5 (+), 30.2 (+) (d, J = 4
Hz), 92.3 (+) (d, J = 8 Hz), 119.6 (+) (d, J = 4 Hz), 124.7 (+), 129.1 (+),
150.6 (–) (d, J = 7 Hz); HRMS (EI+): m/z calcd for C19H25O4P [M+] 348.1490,
found 348.1497.
5.3, 18.4, 23.5, 26.0, 29.4, 36.8, 63.7, 67.8. The 1H and 13C NMR spectra
were identical with those reported.[19]
According to the general procedure for the phosphorylation of an alcohol,
a
mixture of the above alcohol (126 mg, 0.577 mmol), diphenyl
chlorophosphate (0.179 mL, 0.864 mmol), and N-methylimidazole (0.082
mL, 1.04 mmol) in CH2Cl2 (3 mL) was stirred rt for 3 h to produce
phosphate 14a (245 mg, 94% yield): 97.5% ee by HPLC (Chiralpak AD-H,
hexane/iPrOH = 97:3, 1.0 mL/min, 35 °C, tR/min = 10.31 (R-isomer, minor),
11.97 (S-isomer, major)); liquid; Rf 0.26 (hexane/EtOAc 5:1); [α]D21 +5 (c
1.10, CHCl3); IR (neat) 1592, 1491, 1194, 951 cm–1 1H NMR (400 MHz,
;
CDCl3) δ 0.02 (s, 6 H), 0.87 (s, 9 H), 1.36 (t, J = 6.0 Hz, 3 H), 1.45–1.78
(m, 4 H), 3.57 (t, J = 6.4 Hz, 2 H), 4.77 (sept., J = 6.2 Hz, 1 H), 7.15–7.25
(m, 6 H), 7.29–7.36 (m, 4 H); 13C–APT NMR (100 MHz, CDCl3) δ –5.3 (+),
18.4 (–), 21.6 (+) (d, J = 4 Hz), 26.0 (+), 28.3 (–), 33.9 (–) (d, J = 7 Hz),
62.6 (–), 78.4 (+) (d, J = 7 Hz), 120.2 (+) (m), 125.2 (+), 129.8 (+), 150.8
(–) (m); HRMS (FAB+): m/z calcd for C23H36O5PSi [(M+H)+] 451.2070,
found 451.2082.
(S,E)-5-[(tert-Butyldimethylsilyl)oxy]pent-3-en-2-ol (21a): According to
the procedure developed for racemic 3-butyn-2-ol,[18] a mixture of (S)-3-
butyn-2-ol (20) (0.627 mL, 8.00 mmol) (Aldrich, % ee of the derived
compound was determined at a later stage) and a solution of nBuLi (1.60
M in hexane, 15 mL, 24.0 mmol) in THF (40 mL) was stirred at 0 °C for 30
min, and paraformaldehyde (820 mg, 27 mmol) was added. The mixture
was stirred at rt for 15 h and diluted with saturated NH4Cl. The product was
extracted with EtOAc and purified by chromatography on silica gel
(CH2Cl2/acetone 2:1) to afford (S)-pent-2-yne-1,4-diol (637 g, 80% yield):
liquid; Rf 0.17 (CH2Cl2/acetone = 3:1): [α]D21 –31 (c 0.93, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 1.46 (d, J = 6.4 Hz, 3 H), 2.02 (s, 1 H), 2.22 (s, 1 H),
4.30 (s, 2 H), 4.54–4.62 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 24.1, 50.7,
58.1, 82.2, 87.6. To an ice-cold solution of the above diol (401 mg, 4.01
mmol) in THF (20 mL) was added Red-Al (3.6 M in toluene, 2.2 mL, 7.92
mmol) dropwise. The solution was stirred at rt for 1 h, and the reaction was
quenched by addition of NaF (0.80 g, 19 mmol) and water. The resulting
mixture was filtered through a pad of Celite and the filtrate was extracted
with EtOAc three times. The combined extracts were concentrated and the
residue was purified by chromatography on silica gel (CH2Cl2/acetone 2:1)
to give diol (S,E)-pent-2-ene-1,4-diol (315 mg, 77% yield): liquid; Rf 0.16
(S,E)-5-[(tert-Butyldimethylsilyl)oxy]pent-3-en-2-yl diethyl phosphate
(17a): According to the general procedure for the phosphorylation of an
alcohol, a mixture of alcohol 21a (97.9% ee, 291 mg, 1.34 mmol), diethyl
chlorophosphate (0.290 mL, 2.02 mmol), and N-methylimidazole (0.190
mL, 2.41 mmol) in CH2Cl2 (7 mL) was stirred at rt for 5 h to give phosphate
17a (413 mg, 87% yield): liquid; Rf 0.41 (hexane/EtOAc 1:1); [α]D23 –11 (c
1.04, CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.06 (s, 6 H), 0.90 (s, 9 H), 1.31
(dt, J = 1.0, 6.4 Hz, 3 H), 1.32 (dt, J = 1.0, 6.4 Hz, 3 H), 1.41 (d, J = 6.4 Hz,
3 H), 4.03–4.14 (m, 4 H), 4.17 (d, J = 4.0 Hz, 2 H), 4.95 (ddq, J = 6.6, 6.0,
6.4 Hz, 1 H), 5.73 (ddt, J = 15.4, 6.0, 1.4 Hz, 1 H), 5.82 (dt, J = 15.4, 4.0
Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ –5.3, 16.1 (d, J = 7 Hz), 18.4, 22.2
(d, J = 5 Hz), 25.9, 62.7, 63.5 (m), 75.2 (m), 129.5 (d, J = 5 Hz), 131.5. The
1H and 13C NMR spectra were identical with those reported.[8]
6-[(tert-Butyldimethylsilyl)oxy]hex-4-yn-3-ol (rac-23b): To a solution of
propargyl alcohol (1.18 mL, 20.0 mmol) in THF (100 mL) was added nBuLi
(1.60 M in hexane, 25.0 mL, 40.0 mmol) at –40 °C, and the solution was
stirred at the same temperature for 30 min before addition of
propionaldehyde (1.43 mL, 20.0 mmol) dropwise. The solution was
warmed to –10 °C over 2 h, and poured into saturated NH4Cl. The mixture
was extracted with EtOAc 10 times. The combined extracts were washed
with brine, dried over MgSO4, and concentrated. The residue was purified
by chromatography on silica gel (CH2Cl2/acetone 3:1) to afford racemic
hex-2-yne-1,4-diol (1.66 g, 73% yield): liquid; Rf 0.10 (hexane/EtOAc 1:1).
To a solution of the diol (1.65 g, 14.5 mmol) in DMF (73 mL) at –50 °C
were added imidazole (1.18 g, 17.3 mmol) and TBSCl (2.29 g, 15.2 mmol).
The reaction was continued at –50 °C for 1 h, and quenched by addition
of saturated NaHCO3. The resulting mixture was extracted with EtOAc
three times and the combined extracts were washed with brine, dried over
MgSO4, and concentrated. The residue was purified by chromatography
on silica gel to afford rac-23b (2.80 g, 85% yield): liquid; Rf 0.20
(hexane/EtOAc 9:1); 1H NMR (400 MHz, CDCl3) δ 0.10 (s, 6 H), 0.89 (s, 9
H), 0.99 (t, J = 7.2 Hz, 3 H), 1.62–1.78 (m, 2 H), 2.11 (br s, 1 H), 4.30–4.36
(m, 3 H); 13C–APT NMR (100 MHz, CDCl3) δ 5.1 (+), 9.5 (+), 18.3 (–), 25.9
(+), 30.8 (–), 51.8 (–), 63.7 (+), 83.5 (–), 85.7 (–); HRMS (FAB+): m/z calcd
for C12H24O2SiNa [(M+Na)+] 251.1443, found 251.1445.
20
(CH2Cl2/acetone = 2:1): [α]D +6 (c 1.10, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 1.29 (d, J = 6.4 Hz, 3 H), 1.49 (s, 1 H), 1.58 (s, 1 H), 4.16 (s, 2
H), 4.31–4.39 (m, 1 H), 5.79 (dd, J = 15.6, 5.2 Hz, 1 H), 5.84 (dt, J = 15.6,
4.4 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 23.1, 62.5, 68.0, 128.8, 135.5.
A solution of the allylic diol (215 mg, 2.11 mmol), TBSCl (334 mg, 2.22
mmol), and imidazole (172 mg, 2.53 mmol) in DMF (11 mL) was stirred at
–50 °C for 1 h and diluted with saturated NaHCO3. The product was
extracted with EtOAc and purified by chromatography on silica gel
(hexane/EtOAc) to give 21a (416 mg, 91% yield): 97.9% ee by HPLC
(Chiralcel OD-H, hexane/iPrOH = 99:1, 1.0 mL/min, 35 °C, tR/min = 8.99
(R-isomer, minor), 9.91 (S-isomer, major)); liquid; Rf 0.81 (CH2Cl2/acetone
3:1), 0.30 (hexane/EtOAc 5:1); [α]D21 –4 (c 1.1, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 0.07 (s, 6 H), 0.91 (s, 9 H), 1.27 (d, J = 6.0 Hz, 3 H), 1.46 (br s,
1 H), 4.10–4.23 (m, 2 H), 4.29–4.37 (m, 1 H), 5.69–5.80 (m, 2 H); 13C–APT
NMR (100 MHz, CDCl3) δ –5.2 (+), 18.5 (–), 23.3 (+), 26.0 (+), 63.2 (–),
68.3 (+), 129.2 (+), 134.1 (+). The 1H and 13C NMR spectra were identical
with those reported.[18]
(S)-5-[(tert-Butyldimethylsilyl)oxy]pentan-2-yl diphenyl phosphate
(14a): A mixture of allylic alcohol 21a (97.9% ee by HPLC, 372 mg, 1.72
mmol) and 10% Pd/C (36 mg) in EtOH (9 mL) was stirred at rt for 4 h under
hydrogen and filtered through a pad of silica gel. The filtrate was
concentrated to give a residue, which was purified by chromatography on
silica gel (hexane/EtOAc 5:1) to afford (S)-5-(TBS-oxy)pentan-2-ol (172
mg, 46% yield) and the diol. Alcohol S5: liquid; Rf 0.30 (hexane/EtOAc
5:1); [α]D21 +9 (c 1.23, CHCl3); lit.[19] [α]D22.9 –14.4 (c 2.77, CHCl3) for the
(R)-enantiomer; 1H NMR (400 MHz, CDCl3) δ 0.07 (s, 6 H), 0.90 (s, 9 H),
1.19 (d, J = 6.4 Hz, 3 H), 1.42–1.72 (m, 4 H), 2.67 (br d, J = 3.2 Hz, 1 H),
3.61–3.72 (m, 2 H), 3.76–3.86 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ –
(S)-6-[(tert-Butyldimethylsilyl)oxy]hex-4-yn-3-ol (23b): To a solution of
oxalyl chloride (0.823 mL, 9.60 mmol) in CH2Cl2 (35 mL) was added a
solution of DMSO (0.682 mL, 9.60 mmol) at –78 °C. After 5 min of stirring
at –78 °C, rac-23b (1.94 g, 8.00 mmol) in CH2Cl2 (5 mL) was added. After
15 min of stirring at –80 °C, Et3N (6.69 mL, 48.0 mmol) was added. The
resulting mixture was warmed slowly to rt over 30 min, and diluted with
saturated NaHCO3. The mixture was extracted with CH2Cl2 three times.
The combined extracts were washed with brine, dried over MgSO4, and
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10.1002/ejoc.201801596
European Journal of Organic Chemistry
FULL PAPER
concentrated to leave a residue, which was purified by chromatography on
silica gel (hexane/EtOAc 9:1) to afford ketone 22b (1.74 g, 90% yield):
liquid; Rf 0.30 (hexane/EtOAc 19:1); IR (neat) 2211, 1684, 1102, 837 cm–
1; 1H NMR (400 MHz, CDCl3) δ 0.11 (s, 6 H), 0.89 (s, 9 H), 1.11 (t, J = 7.4
Hz, 3 H), 2.56 (q, J = 7.4 Hz, 2 H), 4.44 (s, 2 H); 13C–APT NMR (100 MHz,
CDCl3) δ –5.2 (+), 7.9 (+), 18.2 (–), 25.7 (+), 38.7 (–), 51.5 (–), 83.7 (–),
90.3 (–), 188.0 (–). A mixture of RuCl[(S,S)-TsDPEN](p-cymene) (142 mg,
0.225 mmol) and KOH (ca. 610 mg, 10.9 mmol) in CH2Cl2 (8 mL) was
stirred at rt for 30 min. The mixture was washed with H2O several times
and the CH2Cl2 solution was transferred to another flask with CH2Cl2. The
solution was dried over CaH2. The resulting mixture was filtered and then
concentrated to afford a purple solid. The solid was diluted with iPrOH (2
mL) and ketone 22b (884 mg, 3.90 mmol) in iPrOH (8 mL) was added.
After being stirred at rt for 5 h, the mixture was concentrated to afford a
residue, which was purified by chromatography on silica gel (petroleum
ether/ether 9:1) to give alcohol 23b (550 mg, 62% yield): 96.9% ee by
HPLC of the derived picolinate 38 (Chiralpak IC, hexane/iPrOH = 95:5, 1.0
mL/min, tR/min = 9.35 (S-isomer, major), 10.05 (R-isomer, minor)); liquid;
(S,E)-6-[(tert-Butyldimethylsilyl)oxy]hex-4-en-3-yl diethyl phosphate
(17b): To an ice-cold solution of alcohol 23b (96.9% ee by HPLC, 190 mg,
0.839 mmol) in Et2O (3 mL) was added Red-Al (3.6 M in toluene, 0.700
mL, 2.52 mmol) dropwise. The solution was stirred at 0 °C for 2 h and the
reaction was quenched by addition of 1 N HCl. The resulting mixture was
extracted with Et2O three times. The combined extracts were washed with
saturated NaHCO3 and then brine, dried over MgSO4, and concentrated to
leave a residue, which was purified by chromatography on silica gel
(hexane/EtOAc 4:1) to produce (S,E)-6-(TBS-oxy)hex-4-en-3-ol (80 mg,
41% yield) and the corresponding diol. The product S10: liquid; Rf 0.48
(toluene/EtOAc 5:1); [α]D25 +2 (c 1.03, CHCl3); IR (neat) 3364, 1463, 1255,
837 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.05 (s, 6 H), 0.89 (s, 9 H), 0.90 (t,
J = 7.2 Hz, 3 H), 1.45–1.62 (m, 2 H), 1.90 (br s, 1 H), 4.02 (dt, J = 5.4, 6.6
Hz, 1 H), 4.16 (d, J = 3.8 Hz, 2 H), 5.67 (dd, J = 15.6, 5.4 Hz, 1 H), 5.72
(dt, J = 15.6 Hz, 3.8 Hz, 1 H); 13C–APT NMR (100 MHz, CDCl3) δ –5.2 (+),
9.7 (+), 18.4 (–), 26.0 (+), 30.1 (–), 63.2 (–), 73.7 (+), 73.8 (+), 130.3 (+),
132.8 (+). The 1H NMR spectrum was consistent with that reported.[22]
23
Rf 0.42 (hexane/EtOAc 5:1); [α]D –4 (c 1.17, CHCl3). The 1H NMR
According to the general procedure for the phosphorylation of an alcohol,
spectrum was identical with that of rac-23b.
a
mixture of the above alcohol (67 mg, 0.29 mmol), diethyl
chlorophosphate (0.063 mL, 0.44 mmol), and N-methylimidazole (0.041
mL, 0.52 mmol) in CH2Cl2 (2 mL) was stirred at rt for 3 h to afford 17b (80
mg, 75%): 96.7% ee by HPLC (Chiralpak IC, hexane/iPrOH = 95:5, 1.0
mL/min, 35 °C, tR/min = 9.71 (R-isomer, minor), 10.27 (S-isomer, major):
liquid; Rf 0.23 (hexane/EtOAc 4:1); [α]D24 –9 (c 1.28, CHCl3); 1H NMR (400
MHz, CDCl3) δ 0.04 (s, 6 H), 0.88 (s, 9 H), 0.91 (dt, J = 0.8, 7.4 Hz, 3 H),
1.28 (tt, J = 1.0, 7.2 Hz, 3 H), 1.31 (dt, J = 1.0, 7.2 Hz, 3 H), 1.59–1.81 (m,
2 H), 4.00–4.13 (m, 4 H), 4.17 (d, J = 4.4 Hz, 2 H), 4.71 (quint., J = 7.0 Hz,
OC(O)-2-Py
38, R = Et
39, R = iPr
OTBS
(S)-6-[(tert-Butyldimethylsilyl)oxy]hexan-3-yl diphenyl phosphate
(14b): A mixture of propargylic alcohol 23b (96.9% ee, 150 mg, 0.663
mmol) and 10% Pd/C (19 mg) in MeOH (3 mL) was stirred under hydrogen
at rt for 1 h, and filtered through a pad of silica gel. The filtrate was
concentrated to give a residue, which was purified by chromatography on
silica gel (hexane/EtOAc 1:2) to afford (S)-hexane-1,4-diol (45 mg, 57%
yield): liquid; Rf 0.29 (hexane/EtOAc 1:2); 1H NMR (400 MHz, CDCl3) δ
0.90 (t, J = 7.6 Hz, 3 H), 1.36–1.50 (m, 3 H), 1.54–1.68 (m, 3 H), 3.40–
3.85 (m, 5 H); 13C NMR (100 MHz, CDCl3) δ 10.0, 29.1, 30.2, 33.8, 62.7,
73.1. The 1H and 13C NMR spectra were identical with those reported.[20]
1 H), 5.68 (ddm, J = 15.4, 7.0 Hz, 1 H), 5.82 (dt, J = 15.4, 4.4 Hz, 1 H); 13
C
NMR (100 MHz, CDCl3) δ –5.2, 9.3, 16.2 (d, J = 7 Hz), 18.4, 25.9, 29.2 (d,
J = 5 Hz), 62.8, 63.5 (m), 80.5 (m), 128.0 (d, J = 4 H), 132.9. The 1H and
13C NMR spectra were identical with those reported.[8]
6-[(tert-Butyldimethylsilyl)oxy]-2-methylhex-4-yn-3-ol (rac-23c): To a
solution of propargyl alcohol (2.36 mL, 40.0 mmol) in THF (80 mL) was
added nBuLi (1.55 M in hexane, 50.0 mL, 78.0 mmol) at –40 °C, and the
solution was slowly warmed to –20 °C over 20 min. Isobutyroaldehyde
(3.65 mL, 40.0 mmol) was added and the solution was warmed to 0 °C
over 1 h. Saturated NH4Cl was added and the resulting mixture was
extracted with EtOAc three times. The combined extracts were washed
with brine, dried over MgSO4, and concentrated to afford 5-methylhex-2-
yne-1,4-diol (5.04 g): liquid; Rf 0.21 (hexane/EtOAc 1:1). To a solution of
this diol in DMF (100 mL) at –50 °C were added imidazole (3.21 g, 47.2
mmol) and TBSCl (5.92 g, 39.3 mmol). The mixture was warmed to rt over
1 h, and quenched by addition of saturated NaHCO3. The resulting mixture
was extracted with EtOAc three times and the combined extracts were
washed with brine, dried over MgSO4, and concentrated to afford a residue,
which was purified by chromatography on silica gel to afford rac-23c (7.27
g, 75% yield): liquid; Rf 0.38 (hexane/EtOAc 9:1); 1H NMR (400 MHz,
CDCl3) δ 0.12 (s, 6 H), 0.91 (s, 9 H), 0.98 (d, J = 6.8 Hz, 3 H), 1.00 (d, J =
6.8 Hz, 3 H), 1.78 (d, J = 5.6 Hz, 1 H), 1.87 (d of septet, J = 5.6, 6.8 Hz, 1
H), 4.20 (tt, J = 5.6, 1.6 Hz, 1 H), 4.35 (d, J = 1.6 Hz, 2 H); 13C–APT NMR
(100 MHz, CDCl3) δ –5.1 (+), 17.5 (+), 18.1 (+), 18.3 (–), 25.8 (+), 34.4 (+),
51.8 (–), 67.9 (+), 84.2 (–), 84.6 (–); HRMS (FAB+): m/z calcd for
C13H27O2Si [(M+H)+] 243.1780, found 243.1779.
To a solution of the above diol (45 mg, 0.42 mmol) in DMF (2 mL) were
added imidazole (37 mg, 0.54 mmol) and TBSCl (68 mg, 0.45 mmol) at –
50 °C. After 1 h of stirring at –50 °C, the solution was diluted with saturated
NaHCO3. The mixture was extracted with EtOAc three times. The
combined extracts were washed with brine, dried over MgSO4, and
concentrated to leave a residue, which was purified by chromatography on
silica gel (petroleum ether/ether 3:1) to afford (S)-6-(TBS-oxy)hexan-3-ol
(75 mg, 85% yield): liquid; Rf 0.29 (hexane/EtOAc 4:1); [α]D24 +8 (c 0.80,
CHCl3); lit.[21] [α]D20 –7.5 (c 5.0, CHCl3) for the (R)-enantiomer of 92% ee;
1H NMR (400 MHz, CDCl3) δ 0.07 (s, 6 H), 0.90 (s, 9 H), 0.94 (t, J = 7.4
Hz, 3 H), 1.38–1.53 (m, 3 H), 1.60–1.69 (m, 3 H), 2.52 (d, J = 4.0 Hz, 1 H),
3.49–3.57 (m, 1 H), 3.62–3.71 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ –
5.3, 10.1, 18.4, 26.0, 29.2, 30.1, 34.1, 63.6, 73.0. According to the general
procedure for the phosphorylation of an alcohol, a mixture of the above
alcohol (70 mg, 0.30 mmol), diphenyl chlorophosphate (0.093 mL, 0.45
mmol), N-methylimidazole (0.043 mL, 0.54 mmol) in CH2Cl2 (3 mL) was
stirred at rt for 3 h to afford 14b (121 mg, 87% yield): 96.2% ee by HPLC
(Chiralpak AD-H, hexane/iPrOH = 97:3, 1.0 mL/min, 35 °C, tR/min = 9.76
(R-isomer, minor), 11.01 (S-isomer, major)); liquid; Rf 0.48 (hexane/EtOAc
4:1); [α]D27 +2 (c 1.00, CHCl3); IR (neat) 1592, 1491, 1194, 952 cm–1 1H
;
NMR (300 MHz, CDCl3) δ 0.02 (s, 6 H), 0.87 (s, 9 H), 0.91 (t, J = 7.5 Hz,
3 H), 1.43–1.64 (m, 2 H), 1.64–1.77 (m, 4 H), 3.56 (t, J = 6.2 Hz, 2 H), 4.62
(sext., J = 6.3 Hz, 1 H), 7.13–7.24 (m, 6 H), 7.28–7.36 (m, 4 H); 13C–APT
NMR (75 MHz, CDCl3) δ –5.3 (+), 9.1 (+), 18.3 (–), 26.0 (+), 27.9 (–) (d, J
= 3 Hz), 28.1 (–), 30.8 (–) (d, J = 5 Hz), 62.7 (–), 83.2 (+) (d, J = 7 Hz),
120.2 (+) (d, J = 5 Hz), 125.2 (+), 129.7 (+), 150.8 (–) (d, J = 7 Hz); HRMS
(FAB+): m/z calcd for C24H38O5PSi [(M+H)+] 465.2226, found 465.2231.
(S)-6-[(tert-Butyldimethylsilyl)oxy]-2-methylhex-4-yn-3-ol (23c): To a
solution of oxalyl chloride (0.310 mL, 3.61 mmol) in CH2Cl2 (10 mL) was
added a solution of DMSO (0.256 mL, 3.61 mmol) at –78 °C. After 5 min
of stirring at –78 °C, alcohol rac-23c (730 mg, 3.01 mmol) in CH2Cl2 (5 mL)
was added. After 15 min of stirring at –78 °C, Et3N (2.52 mL, 18.1 mmol)
was added. The solution was warmed slowly to rt over 30 min, and diluted
with saturated NaHCO3. The mixture was extracted with CH2Cl2 three
times. The combined extracts were washed with brine, dried over MgSO4,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801596
European Journal of Organic Chemistry
FULL PAPER
and concentrated to leave
a
residue, which was purified by
CDCl3) δ –5.2(+), 18.0 (+), 18.2 (+), 18.4 (–), 26.0 (+), 33.8 (+), 63.3 (–),
77.5 (+), 131.1 (+). According to the general procedure for the
phosphorylation of an alcohol, a mixture of the above alcohol (130 mg,
0.532 mmol), diethyl chlorophosphate (0.115 mL, 0.798 mmol), and N-
methylimidazole (0.076 mL, 0.96 mmol) in CH2Cl2 (5 mL) was stirred at rt
for 3 h to produce 17c (140 mg, 69% yield): 96.5% ee by HPLC (Chiralpak
IC, hexane/iPrOH = 95:5, 1.0 mL/min, tR/min = 8.30 (R-isomer, minor),
8.91 (S-isomer, major): liquid; Rf 0.26 (hexane/EtOAc 4:1); [α]D24 –2 (c 1.37,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.06 (s, 6 H), 0.90 (s, 9 H), 0.91 (d,
J = 6.8 Hz, 3 H), 0.93 (d, J = 6.8 Hz, 3 H), 1.29 (dt, J = 1.0, 7.2 Hz, 3 H),
1.32 (dt, J = 1.0, 7.2 Hz, 3 H), 1.92 (d of sept., J = 6.0, 6.8 Hz, 1 H), 4.00–
4.15 (m, 4 H), 4.18 (dd, J = 4.2, 1.8 Hz, 2 H), 4.57 (dt, J = 6.0, 7.6 Hz, 1
H), 5.73 (ddt, J = 15.4, 7.6, 1.8 Hz, 1 H), 5.83 (dt, J = 15.4, 4.2 Hz, 1 H);
13C NMR (100 MHz, CDCl3) δ –5.3, 16.10 (d, J = 7 Hz), 16.14 (d, J = 7 Hz),
17.6, 18.0, 18.3, 25.9, 33.3 (d, J = 7 Hz), 62.7, 63.4 (d, J = 5 Hz), 84.0 (d,
J = 6 Hz), 126.1 (d, J = 3 Hz), 133.8. The 1H and 13C NMR spectra were
identical with those reported.[8]
chromatography on silica gel (hexane/EtOAc 9:1) to afford ketone 22c
(500 mg, 69% yield): liquid; Rf 0.75 (hexane/EtOAc 4:1); 1H NMR (400
MHz, CDCl3) δ 0.13 (s, 6 H), 0.91 (s, 9 H), 1.19 (d, J = 6.8 Hz, 6 H), 2.65
(sept., J = 6.8 Hz, 1 H), 4.48 (s, 2 H); 13C NMR (100 MHz, CDCl3) δ –5.2,
17.8, 18.2, 25.7, 42.9, 51.5, 82.9, 91.2.
A mixture of RuCl[(S,S)-
TsDPEN](p-cymene) (54 mg, 0.085 mmol) and KOH (ca. 500 mg, 8.9
mmol) in CH2Cl2 (10 mL) was stirred at rt for 30 min. The mixture was
washed with H2O several times and the CH2Cl2 solution was transferred to
another flask with CH2Cl2. The solution was dried over CaH2. The resulting
mixture was filtered and then concentrated to afford a purple solid. The
solid was diluted with iPrOH (10 mL) and ketone 22c (1.00 g, 4.16 mmol)
in iPrOH (5 mL) was added. After being stirred at rt for 3 h, the mixture was
concentrated to afford a residue, which was purified by chromatography
on silica gel (hexane/EtOAc) to give alcohol 23c (606 mg, 60% yield):
97.9% ee by HPLC of the derived picolinate 39 (Chiralpak IC,
hexane/iPrOH = 95:5, 1.0 mL/min, 35 °C, tR/min = 13.50 (R-isomer, minor),
15.05 (S-isomer, major)); liquid; Rf 0.50 (hexane/EtOAc 4:1). The 1H NMR
spectrum was identical with that of rac-23c.
Cyclohexyl diphenyl phosphate (24a): According to the general
procedure for the phosphorylation of an alcohol, a mixture of cyclohexanol
(100 mg, 1.00 mmol), diphenyl chlorophosphate (0.21 mL, 1.02 mmol), and
N-methylimidazole (0.087 mL, 1.10 mmol) in CH2Cl2 (1 mL) was stirred at
rt for 11 h to afford phosphate 24a (264 mg, 79% yield): liquid; Rf 0.70
(hexane/EtOAc 1:1); 1H NMR (400 MHz, CDCl3) δ 1.19–1.39 (m, 3 H),
1.45–1.64 (m, 3 H), 1.67–1.79 (m, 2 H), 1.89–2.00 (m, 2 H), 4.62 (dtt, J =
6.8, 9.0, 3.9 Hz, 1 H), 7.18 (t, J = 7.6 Hz, 2 H), 7.23 (d, J = 7.6 Hz, 4 H),
7.33 (t, J = 7.6 Hz, 4 H); 13C–APT NMR (100 MHz, CDCl3) δ 23.3 (–), 25.0
(–), 33.1 (–) (d, J = 5 Hz), 79.4 (+) (d, J = 6 Hz), 120.1 (+) (d, J = 5 Hz),
(R)-6-[(tert-Butyldimethylsilyl)oxy]-2-methylhexan-3-yl
diphenyl
phosphate (14c): A mixture of propargylic alcohol 23c (97.9% ee by
HPLC, 2.21 g, 9.17 mmol) and 10% Pd/C (221 mg) in MeOH (46 mL) was
stirred under hydrogen at rt for 1 h, and filtered through a pad of silica gel.
The filtrate was concentrated, and the residue was purified by
chromatography on silica gel (hexane/EtOAc 9:1) to afford (R)-6-(TBS-
oxy)-2-methylhexan-3-ol (1.53 g, 70% yield): liquid; Rf 0.17 (hexane/EtOAc
9:1); [α]D24 +8 (c 0.70, CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.06 (s, 6 H),
0.89–0.94 (m, 15 H), 1.33–1.52 (m, 1 H), 1.56–1.73 (m, 4 H), 2.39 (d, J =
4.4 Hz, 1 H), 3.32–3.40 (m, 1 H), 3.66 (t, J = 6.0 Hz, 2 H); 13C NMR (100
MHz, CDCl3) δ –5.3, 17.7, 18.4, 18.8, 26.0, 29.4, 31.1, 33.6, 63.6, 76.4.
The 1H and 13C NMR spectra were identical with those reported.[23]
125.1 (+) (d, J = 1 Hz), 129.7 (+), 150.7 (–) (d, J = 7 Hz). The 1H and 13
NMR spectra were consistent with those reported.[17,24]
C
(1s,4s)-4-(tert-Butyl)cyclohexyl diphenyl phosphate (24b): According
to the literature procedure,[25] a THF solution of L-Selectride (1.02 M, 4.10
mL, 4.18 mmol) was added to a solution of 4-tert-butylcyclohexanone (421
mg, 2.73 mmol) in THF (5 mL) at –90 °C. The solution was slowly warmed
to rt and stirred for 12 h. Water (1.0 mL, 56 mmol), 30% H2O2 (1.0 mL),
and aqueous NaOH (3 N, 1.0 mL) were added to the solution. The resulting
mixture was extracted with Et2O several times. The combined extracts
were washed with brine, dried (MgSO4), and concentrated to leave a
mixture of the cis and trans isomers of 4-(tert-butyl)cyclohexan-1-ol in a
ratio of 95:5 by 1H NMR spectroscopy (δ 4.00–4.07 and 3.46–3.58).
Chromatography of the products on silica gel (hexane/EtOAc 10:1)
afforded the cis-isomer (343 mg, 80% yield): liquid; Rf 0.25 (hexane/EtOAc
4:1); 1H NMR (400 MHz, CDCl3) δ 0.86 (s, 9 H), 0.99 (tt, J = 11.6, 3.0 Hz,
1 H), 1.28 (br s, 1 H), 1.30–1.42 (m, 2 H), 1.43–1.58 (m, 4 H), 1.78–1.88
(m, 2 H), 4.00–4.07 (m, 1 H). The 1H NMR spectrum was consistent with
that reported.[26] The 1H NMR data reported in ref. 25 were updated.
According to the general procedure for the phosphorylation of an alcohol,
a
mixture of the above alcohol (66 mg, 0.27 mmol), diphenyl
chlorophosphate (0.083 mL, 0.40 mmol), and N-methylimidazole (0.038
mL, 0.48 mmol) in CH2Cl2 (3 mL) was stirred at rt for 3 h to give 14c (115
mg, 89% yield): 96.3% ee by HPLC (Chiralpak AD-H, hexane/iPrOH = 97:3,
1.0 mL/min, 35 °C, tR/min = 8.84 (R-isomer, minor), 9.74 (S-isomer, major);
23
liquid; Rf 0.20 (hexane/EtOAc 9:1); [α]D +3 (c 1.01, CHCl3); IR (neat)
1491, 1194, 1014, 951 cm–1 1H NMR (400 MHz, CDCl3) δ 0.02 (s, 6 H),
;
0.87 (s, 9 H), 0.91 (d, J = 6.8 Hz, 3 H), 0.92 (d, J = 6.8 Hz, 3 H), 1.45–1.73
(m, 4 H), 1.94–2.04 (m, 1 H), 3.51–3.61 (m, 2 H), 4.51 (quint., J = 6.0 Hz,
1 H), 7.17 (t, J = 7.6 Hz, 2 H), 7.22 (d, J = 7.6 Hz, 4 H), 7.32 (t, J = 7.6 Hz,
4 H); 13C–APT NMR (100 MHz, CDCl3) δ –5.3 (+), 17.4 (+), 17.9 (+), 25.9
(+), 28.0 (–) (d, J = 4 Hz), 28.3 (–), 31.9 (+) (d, J = 5 Hz), 62.6 (–), 86.7 (+)
(d, J = 7 Hz), 120.1 (d, J = 4 Hz), 125.1 (+), 129.7 (+), 150.8 (–) (d, J = 8
Hz); HRMS (FAB+): m/z calcd for C25H40O5PSi [(M+H)+] 479.2383, found
479.2373.
According to the general procedure for the phosphorylation of an alcohol,
a mixture of the cis isomer (343 mg, 2.19 mmol), diphenyl chlorophosphate
(0.68 mL, 3.29 mmol), and N-methylimidazole (0.31 mL, 3.93 mmol) in
CH2Cl2 (5 mL) was stirred at rt for 3 h, and the reaction was quenched by
adding Me2N(CH2)3NH2 (excess) at 0 °C. After 1 h of stirring at rt, saturated
NaHCO3 was added and the resulting mixture was extracted with EtOAc
three times. The combined extracts were washed with brine, dried over
MgSO4, and concentrated to leave a residue, which was purified by
chromatography on silica gel (hexane/EtOAc 10:1) to afford 24b (730 mg,
86% yield): solids; mp 58–59 °C; Rf 0.41 (hexane/EtOAc 4:1); IR (nujol)
1592, 1490, 1283, 1193, 1016, 953 cm–1; 1H NMR (400 MHz, CDCl3) δ
0.82 (s, 9 H), 0.99 (tt, J = 12.0, 3.0 Hz, 1 H), 1.21–1.36 (m, 2 H), 1.41–1.58
(m, 4 H), 2.00–2.11 (m, 2 H), 4.87–4.95 (m, 1 H), 7.18 (t, J = 7.6 Hz, 2 H),
7.24 (d, J = 7.6 Hz, 4 H), 7.33 (t, J = 7.6 Hz, 4 H); 13C–APT NMR (100
MHz, CDCl3) δ 21.0 (–), 27.4 (+), 32.0 (–) (d, J = 5 Hz), 32.6 (–), 47.3 (+),
76.9 (+) (d, J = 8 Hz), 120.2 (+) (d, J = 3 Hz), 125.2 (+), 129.7 (+), 150.8
(S,E)-6-[(tert-Butyldimethylsilyl)oxy]-2-methylhex-4-en-3-yl
diethyl
phosphate (17c): To an ice-cold solution of alcohol 23c (97.9% ee by
HPLC, 180 mg, 0.742 mmol) in Et2O (5 mL) was added Red-Al (3.6 M in
toluene, 0.620 mL, 2.23 mmol) dropwise. The solution was stirred at 0 °C
for 2 h and the reaction was quenched by addition of 1 N HCl. The resulting
mixture was extracted with EtOAc three times. The combined extracts
were washed with saturated NaHCO3 and then brine, dried over MgSO4,
and concentrated to leave
a
residue, which was purified by
chromatography on silica gel (hexane/EtOAc 4:1) to produce (S,E)-6-
(TBS-oxy)-2-methylhex-4-en-3-ol (132 mg, 73% yield): liquid; Rf 0.50
(hexane/EtOAc 4:1); [α]D23 +9 (c 0.95, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 0.07 (s, 6 H), 0.89 (d, J = 6.8 Hz, 3 H), 0.91 (s, 9 H), 0.93 (d, J = 6.8 Hz,
3 H), 1.48 (br s, 1 H), 1.73 (octet, J = 6.8 Hz, 1 H), 3.85–3.91 (m, 1 H),
4.19 (d, J = 2.8 Hz, 1 H), 5.68–5.79 (m, 2 H); 13C–APT NMR (100 MHz,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801596
European Journal of Organic Chemistry
FULL PAPER
(–) (d, J = 7 Hz); HRMS (FAB+): m/z calcd for C22H30O4P [(M+H)+]
389.1882, found 389.1886.
4 H); 13C–APT NMR (75 MHz, CDCl3) δ 21.6 (+), 31.2 (+), 32.8 (–), 33.2
(–) (d, J = 5 Hz), 80.1 (+) (d, J = 7 Hz), 120.9 (+) (d, J = 5 Hz), 125.1 (+),
129.7 (+), 150.6 (–) (d, J = 8 Hz); HRMS (FAB+): m/z calcd for C19H24O4P
[(M+H)+] 347.1412, found 347.1422.
(1r,4r)-4-(tert-Butyl)cyclohexyl diphenyl phosphate (24d): According to
the literature procedure,[25] a solution of 4-tert-butylcyclohexanone (410
mg, 2.66 mmol) in Et2O (5 mL) was added dropwise to an ice-cold
suspension of LiAlH4 (152 mg, 4.01 mmol) in Et2O (5 mL). The resulting
solution was stirred at rt 0 °C for 2 h and excess hydride was quenched by
carefully adding H2O. The resulting mixture was filtered through a pad of
Celite. The filtrate was concentrated to leave a mixture of the trans and cis
isomers of 4-(tert-butyl)cyclohexan-1-ol in a ratio of 92:8 by 1H NMR
spectroscopy (δ 3.46–3.58 and 4.01–4.06). Chromatography of the
mixture on silica gel (hexane/EtOAc 10:1) gave the trans isomer (332 mg,
80% yield): liquid; Rf 0.32 (hexane/EtOAc 4:1); 1H NMR (400 MHz, CDCl3)
δ 0.85 (s, 9 H), 0.94–1.11 (m, 3 H), 1.16–1.28 (m, 2 H), 1.39 (br s, 1 H),
1.74–1.83 (m, 2 H), 1.96–2.06 (m, 2 H), 3.46–3.58 (m, 1 H). The 1H NMR
spectrum was consistent with that reported.[26] The 1H NMR data reported
in ref. 25 were updated.
(1S*,3R*)- and (1R*,3R*)-3-Methylcyclohexyl diphenyl phosphates
(24f) and (24g): According to the synthesis of 4-methylcyclohexan-1-ol,
NaBH4 (296 mg, 7.82 mmol) was added to an ice-cold solution of 3-
methylcyclohexanone (423 mg, 3.77 mmol) in MeOH (10 mL), and the
solution was stirred at 0 °C for 1 h to afford the cis (major) and trans (minor)
mixture of 3-methylcyclohexan-1-ol[26,27] for the next reaction. According to
the general procedure for the phosphorylation of an alcohol, this alcohol,
diphenyl chlorophosphate (1.17 mL, 5.67 mmol), and N-methylimidazole
(0.577 mL, 6.79 mmol) in CH2Cl2 (10 mL) was stirred at rt for 16 h to afford
24f (611 mg, 47% yield over two steps) and 24g (238 mg, 18% yield).
Phosphate 24f: mp 63–64 °C; Rf 0.52 (hexane/EtOAc 4:1); IR (nujol) 1591,
1490, 1193, 1020, 952 cm–1; 1H NMR (300 MHz, CDCl3) δ 0.71–0.99 (m,
1 H), 0.96 (d, J = 6.3 Hz, 3 H), 1.13 (q, J = 11.7 Hz, 1 H), 1.18–1.65 (m, 4
H), 1.71–1.82 (m, 1 H), 2.00–2.16 (m, 2 H), 4.44–4.62 (m, 1 H), 7.14–7.29
(m, 6 H), 7.29–7.40 (m, 4 H); 13C–APT NMR (75 MHz, CDCl3) δ 22.1 (+),
23.8 (–), 31.4 (+), 33.1 (–) (d, J = 5 Hz), 33.5 (–), 42.1 (–) (d, J = 5 Hz),
79.9 (+) (d, J = 6 Hz), 120.1 (+) (d, J = 5 Hz), 125.2 (+), 129.7 (+), 150.6
(–) (d, J = 8 Hz); HRMS (FAB+): m/z calcd for C19H24O4P [(M+H)+]
347.1412, found 347.1419. Phosphate 24g: liquid; Rf 0.39 (hexane/EtOAc
4:1); IR (neat) 1591, 1490, 1193, 1015, 952 cm–1; 1H NMR (300 MHz,
CDCl3) δ 0.83 (d, J = 6.3 Hz, 3 H), 0.87–0.99 (m, 1 H), 1.08–1.24 (m, 1 H),
1.36–1.82 (m, 5 H), 1.84–1.97 (m, 2 H), 4.92–5.01 (m, 1 H), 7.14–7.29 (m,
6 H), 7.29–7.40 (m, 4 H); 13C–APT NMR (75 MHz, CDCl3) δ 20.0 (–), 22.0
(+), 26.4 (+), 31.2 (–) (d, J = 4.6 Hz), 33.9 (–), 39.7 (–) (d, J = 4.6 Hz), 77.7
(+) (d, J = 5.7 Hz), 120.1 (+) (d, J = 5.8 Hz), 125.2 (+), 129.7 (+), 150.7 (–)
(d, J = 8.0 Hz); HRMS (FAB+): m/z calcd for C19H24O4P [(M+H)+] 347.1412,
found 347.1415.
According to the general procedure for the phosphorylation of an alcohol,
a
mixture of the trans isomer (332 mg, 2.12 mmol), diphenyl
chlorophosphate (0.66 mL, 3.19 mmol), and N-methylimidazole (0.30 mL,
3.80 mmol) in CH2Cl2 (5 mL) was stirred at rt for 3 h, and the reaction was
quenched by adding Me2N(CH2)3NH2 (excess) at 0 °C. After 1 h of stirring
at rt, saturated NaHCO3 was added and the resulting mixture was
extracted with EtOAc three times. The combined extracts were washed
with brine, dried over MgSO4, and concentrated to leave a residue, which
was purified by chromatography on silica gel (hexane/EtOAc 10:1) to
afford 24d (702 mg, 85% yield): liquid; Rf 0.48 (hexane/EtOAc 4:1); IR
(neat) 1591, 1490, 1193, 952, 755 cm–1;1H NMR (400 MHz, CDCl3) δ 0.83
(s, 9 H), 0.97 (tt, J = 11.6, 2.8 Hz, 1 H), 1.07 (dq, J = 2.8, 13.2 Hz, 2 H),
1.47 (dq, J = 3.2, 12.0 Hz, 2 H), 1.74–1.86 (m, 2 H), 2.09–2.21 (m, 2 H),
4.47 (dtt, J = 6.8, 11.2, 4.8 Hz, 1 H), 7.15–7.24 (m, 6 H), 7.30–7.36 (m, 4
H); 13C–APT NMR (100 MHz, CDCl3) δ 25.5 (–), 27.6 (+), 32.3 (–), 33.8 (–)
(d, J = 5 Hz), 46.7 (+), 80.5 (–) (d, J = 7 Hz), 120.2 (+), 125.2 (+), 129.8
(+), 150.8 (–), (d, J = 8 Hz); HRMS (FAB+): m/z calcd for C22H30O4P
[(M+H)+] 389.1882, found 389.1870.
(1S*,2R*)- and (1R*,2R*)-2-Methylcyclohexyl diphenyl phosphate
(24h) and (24i): According to the synthesis of 4-methylcyclohexan-1-ol,
NaBH4 (204 mg, 5.39 mmol) was added to an ice-cold solution of 2-
methylcyclohexanone (294 mg, 2.62 mmol) in MeOH (5 mL) and the
solution was stirred at 0 °C for 1 h to afford a stereoisomeric mixture of 2-
methylcyclohexan-1-ol.[26,28] According to the general procedure for the
phosphorylation of an alcohol, a mixture of the above alcohol, diphenyl
chlorophosphate (0.811 mL, 3.93 mmol), and N-methylimidazole (0.373
mL, 4.72 mmol) in CH2Cl2 (5 mL) was stirred at rt for 3 h to give 24h (402
mg, 44% yield over two steps) and 24i (387 mg, 43% yield). Phosphate
24h: liquid; Rf 0.40 (hexane/EtOAc 4:1); IR (neat) 1592, 1490, 1193, 951
cm–1;1H NMR (300 MHz, CDCl3) δ 0.91 (d, J = 6.9 Hz, 3 H), 1.18–1.80 (m,
8 H), 1.89–2.10 (m, 1 H), 4.68–4.81 (m, 1 H), 7.14–7.29 (m, 6 H), 7.30–
7.38 (m, 4 H); 13C–APT NMR (75 MHz, CDCl3) δ 17.1 (+), 20.4 (–), 24.2
(–), 28.8 (–), 31.0 (–), 35.6 (+) (d, J = 6 Hz), 81.8 (+) (d, J = 7 Hz), 120.05
(+) (d, J = 5 Hz), 120.11 (+) (d, J = 3 Hz), 125.1 (+), 129.6 (+), 150.7 (–)
(d, J = 7 Hz); HRMS (FAB+): m/z calcd for C19H24O4P [(M+H)+] 347.1412,
found 347.1412. Phosphate 24i: liquid; Rf 0.47 (hexane/EtOAc 4:1); IR
(neat) 1591, 1490, 1285, 1193 cm–1; 1H NMR (300 MHz, CDCl3) δ 0.95 (d,
J = 6.6 Hz, 3 H), 0.90–1.67 (m, 6 H), 1.70–1.80 (m, 2 H), 2.10–2.22 (m, 1
H), 4.10–4.24 (m, 1 H), 7.14–7.29 (m, 6 H), 7.29–7.40 (m, 4 H); 13C–APT
NMR (75 MHz, CDCl3) δ 18.5 (+), 24.7 (–), 24.9 (–), 33.2 (–), 33.3 (–), 38.5
(+) (d, J = 7 Hz), 85.8 (+) (d, J = 7 Hz), 120.1 (+) (d, J = 6 Hz), 120.2 (+)
(d, J = 5 Hz), 125.1 (+), 129.7 (+), 150.7 (–) (d, J = 8 Hz); HRMS (FAB+):
m/z calcd for C19H24O4P [(M+H)+] 347.1412, found 347.1412.
(1s,4s)- and (1r,4r)-4-Methylcyclohexyl diphenyl phosphates (24c)
and (24e): To an ice-cold solution of 4-methylcyclohexanone (435 mg,
3.89 mmol) in MeOH (10 mL) was added NaBH4 (325 mg, 8.59 mmol). The
solution was stirred at 0 °C for 1 h and diluted with saturated NH4Cl. The
resulting mixture was extracted with Et2O four times. The combined
extracts were washed with brine, dried over MgSO4, and concentrated to
leave a residue, which was diluted with CH2Cl2 and filtered through a pad
of silica gel to afford the cis (major) and trans (minor) mixture of 4-
methylcyclohexan-1-ol[26] for the next reaction. According to the general
procedure for the phosphorylation of an alcohol, a mixture of the above
alcohol, diphenyl chlorophosphate (1.20 mL, 5.84 mmol), and N-
methylimidazole (0.553 mL, 7.00 mmol) in CH2Cl2 (10 mL) was stirred at rt
for 16 h, and the product was purified by chromatography on silica gel
(hexane/EtOAc 4:1) to afford 24c (773 mg, 57% yield over two steps) and
24e (258 mg, 19% yield). Phosphate 24c: liquid; Rf 0.37 (hexane/EtOAc
4:1); IR (neat) 1591, 1490, 1193, 1014, 951 cm–1; 1H NMR (300 MHz,
CDCl3) δ 0.89 (d, J = 6.0 Hz, 3 H), 1.18–1.78 (m, 7 H), 1.90–2.02 (m, 2 H),
4.84–4.93 (m, 1 H), 7.15–7.27 (m, 6 H), 7.30–7.38 (m, 4 H); 13C–APT NMR
(75 MHz, CDCl3) δ 22.0 (+), 28.6 (–), 30.9 (–), 31.1 (+) (d, J = 6 Hz), 77.0
(+), 120.1 (+) (d, J = 5 Hz), 125.1 (+), 129.7 (+), 150.6 (–) (d, J = 7 Hz);
HRMS (FAB+): m/z calcd for C19H24O4P [(M+H)+] 347.1412, found
347.1422. Phosphate 24e: solids; mp 47–48 °C; Rf 0.47 (hexane/EtOAc
4:1); IR (nujol) 1591, 1490, 1193, 951 cm–1; 1H NMR (300 MHz, CDCl3) δ
0.87 (d, J = 6.3 Hz, 3 H), 1.00 (dq, J = 3.3, 13.2 Hz, 2 H), 1.23–1.42 (m, 1
H), 1.50 (dq, J = 3.9, 12.6 Hz, 2 H), 1.64–1.80 (m, 2 H), 2.02–2.16 (m, 2
H), 4.20 (dtt, J = 6.9, 11.1, 4.5 Hz, 1 H), 7.14–7.29 (m, 6 H), 7.29–7.40 (m,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801596
European Journal of Organic Chemistry
FULL PAPER
OTBDPS
OTBDPS
OTBDPS
(3S,5S,8R,9S,10S,13S,14S,17S)-17-[(tert-Butyldiphenylsilyl)oxy]-
10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl
diphenyl phosphate (29): To a solution of 40 (100 mg, 0.189 mmol) in
MeOH (3 mL) was added NaBH4 (24 mg, 0.63 mmol) at –78 °C. The
solution was warmed to 0 °C over 2 h and diluted with saturated NH4Cl.
The resulting mixture was extracted with EtOAc three times. The combined
extracts were washed with brine, dried over MgSO4, and concentrated to
leave a residue, which was purified by chromatography on silica gel
(hexane/EtOAc 4:1) to afford 42 (74 mg, 78% yield) and 41 (7 mg, 6%
H
H
H
H
H
H
H
H
H
O
HO
HO
H
H
H
40
41
42
(5S,8R,9S,10S,13S,14S,17S)-17-[(tert-Butyldiphenylsilyl)oxy]-10,13-
dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one (40): A
solution of stanolone (165 mg, 0.568 mmol), TBDPSCl (0.321 mL, 1.23
mmol), DMAP (33 mg, 0.27 mmol), imidazole (124 mg, 1.82 mmol), and
TBDPSCl (0.321 mL, 1.23 mmol) in CH2Cl2 (4 mL) was stirred at rt for 5 h,
and diluted with saturated NaHCO3. The mixture was extracted with EtOAc
three times. The combined extracts were washed with brine, dried over
MgSO4, and concentrated to leave a residue, which was purified by
chromatography on silica gel (hexane/EtOAc 9:1) to afford TBDPS ether
40 (289 mg, 96% yield): solids; mp 163–164 °C; lit.[29] mp 156–158 °C; Rf
0.27 (hexane/EtOAc 9:1); 1H NMR (400 MHz, CDCl3) δ 0.63 (ddd, J = 12.4,
10.8, 4.2 Hz, 1 H), 0.71–0.86 (m, 3 H), 0.88 (s, 3 H), 1.01 (s, 3 H), 1.08 (s,
9 H), 1.14–1.78 (m, 13 H), 1.96–2.11 (m, 2 H), 2.21–2.43 (m, 3 H), 3.63 (t,
J = 8.4 Hz, 1 H), 7.33–7.45 (m, 6 H), 7.64–7.70 (m, 4 H); 13C NMR (100
MHz, CDCl3) δ 11.5, 11.8, 19.4, 21.1, 23.6, 27.1, 28.9, 30.8, 31.3, 35.5,
35.7, 37.0, 38.2, 38.6, 43.8, 44.8, 46.8, 50.1, 53.9, 82.5, 127.40, 127.45,
129.48, 129.53, 134.4, 134.9, 136.00, 136.05, 212.1. The 1H and 13C NMR
spectra were identical with those reported.[29]
21
yield). Alcohol 42: gum; Rf 0.37 (hexane/EtOAc 4:1); [α]D –14 (c 0.80,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.52 (ddd, J = 12.0, 10.4, 4.0 Hz, 1
H), 0.69–0.79 (m, 3 H), 0.80 (s, 3 H), 0.85 (s, 3 H), 0.87–0.97 (m, 2 H),
1.07 (s, 9 H), 1.10–1.83 (m, 17 H), 3.56 (tt, J = 10.8, 5.0 Hz, 1 H), 3.61 (t,
J = 8.2 Hz, 1 H), 7.33–7.45 (m, 6 H), 7.64–7.69 (m, 4 H); 13C NMR (100
MHz, CDCl3) δ 11.8, 12.4, 19.4, 21.0, 23.6, 27.1, 28.6, 30.9, 31.5, 31.7,
35.6, 37.07, 37.11, 38.2, 43.8, 44.9, 50.3, 54.5, 71.3, 82.6, 127.40, 127.43,
129.4, 129.5, 134.5, 135.0, 136.0, 136.1. The 1H and 13C NMR spectra
were identical with those reported.[29]
According to the general procedure for the phosphorylation of an alcohol,
a mixture of the alcohol 42 (84 mg, 0.16 mmol), diphenyl chlorophosphate
(0.050 mL, 0.24 mmol), and N-methylimidazole (0.023 mL, 0.29 mmol) in
CH2Cl2 (3 mL) was stirred at rt for 2 h to afford 29 (111 mg, 92% yield):
19
liquid; Rf 0.43 (hexane/EtOAc 4:1); [α]D –12 (c 2.03, CHCl3); IR (neat)
1490, 1193, 1015, 952 cm–1; 1H NMR (300 MHz, CDCl3) δ 0.46–0.59 (m,
1 H), 0.66–1.84 (m, 20 H), 0.82 (s, 3 H), 0.85 (s, 3 H), 1.08 (s, 9 H), 1.88–
2.00 (m, 1 H), 3.62 (t, J = 8.3 Hz, 1 H), 4.44–4.61 (m, 1 H), 7.14–7.29 (m,
6 H), 7.29–7.47 (m, 10 H), 7.64–7.71 (m, 4 H); 13C–APT NMR (75 MHz,
CDCl3) δ 11.8 (+), 12.3 (+), 19.4 (–), 20.9 (–), 23.5 (–), 27.1 (+), 28.4 (–),
29.3 (d, J = 5 Hz) (–), 30.8 (–), 31.5 (–), 35.4 (–), 35.5 (+), 35.7 (d, J = 5
Hz) (–), 36.8 (–), 37.0 (–), 43.7 (–), 44.7 (+), 50.2 (+), 54.2 (+), 80.4 (d, J =
7 Hz) (+), 82.5 (+), 120.2 (d, J = 5 Hz) (+), 125.2 (+), 127.39 (+), 127.44
(+), 129.45 (+), 129.51 (+), 129.7 (+), 134.4 (–), 135.0 (–), 135.99 (+),
136.04 (+), 150.7 (d, J = 7 Hz) (–); HRMS (FAB+): m/z calcd for
C47H59O5PSiNa [(M+Na)+] 785.3767, found 785.3740.
(3R,5S,8R,9S,10S,13S,14S,17S)-17-[(tert-Butyldiphenylsilyl)oxy]-
10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl
diphenyl phosphate (27): To a solution of 40 (100 mg, 0.189 mmol) in
THF (3 mL) was added a THF solution of L-Selectride (1.02 M, 0.750 mL,
0.756 mmol) dropwise at –78 °C. The solution was warmed slowly to –
20 °C over 2 h, and aqueous 1 N NaOH (1.5 mL, 1.5 mmol) and H2O2 (35
wt % in H2O, 0.13 mL, 1.5 mmol) were added. The mixture was stirred at
–20 °C for 1 h and diluted with saturated NH4Cl. The mixture was extracted
with EtOAc four times. The combined organic layers were washed with
brine, dried over MgSO4, and concentrated to give a residue, which was
purified by chromatography on silica gel (hexane/EtOAc 4:1) to afford 41
(71 mg, 71% yield) and 42 (9 mg, 9% yield). Alcohol 41: gum; Rf 0.48
(hexane/EtOAc 4:1); [α]D21 –14 (c 0.81, CHCl3); IR (neat) 3412, 1216, 1113,
759, 703 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.65 (ddd, J = 12.4, 10.8, 4.0
Hz, 1 H), 0.72–0.84 (m, 3 H), 0.78 (s, 3 H), 0.86 (s, 3 H), 1.08 (s, 9 H),
1.10–1.77 (m, 19 H), 3.63 (t, J = 8.2 Hz, 1 H), 4.00–4.05 (m, 1 H), 7.33–
7.45 (m, 6 H), 7.65–7.70 (m, 4 H); 13C–APT NMR (100 MHz, CDCl3) δ 11.3
(+), 11.8 (+), 19.4 (–), 20.5 (–), 23.6 (–), 27.1 (+), 28.5 (–), 29.1 (–), 30.9
(–), 31.6 (–), 32.2 (–), 35.6 (+), 35.9 (–), 36.2 (–), 37.1 (–), 39.2 (+), 43.8
(–), 50.4 (+), 54.5 (+), 66.6 (+), 82.6 (+), 127.40 (+), 127.44 (+), 129.4 (+),
129.5 (+), 134.5 (–), 135.1 (–), 136.0 (+), 136.1 (+). According to the
general procedure for the phosphorylation of an alcohol, a mixture of the
above alcohol 41 (80 mg, 0.15 mmol), diphenyl chlorophosphate (0.050
mL, 0.24 mmol), and N-methylimidazole (0.023 mL, 0.29 mmol) in CH2Cl2
(3 mL) was stirred at rt for 2 h to afford 27 (109 mg, 95% yield): liquid; Rf
0.29 (hexane/EtOAc 4:1); [α]D19 –11 (c 0.92, CHCl3); IR (neat) 1490, 1192,
AcO
OTBS Ph
Ph
OH
OR
43
46
44, R = TBS
45, R = H
AcO
OH
Ph
OH
Ph
OH
48
47
49
Diphenyl [(1S*,3R*)-3-phenylcyclopentyl] phosphate (31): To
a
suspension of CuCN (25 mg, 0.28 mmol) in THF (5 mL) was added a
solution of PhMgCl (0.77 M in THF, 3.60 mL, 2.77 mmol) at –20 °C. The
mixture was stirred for 20 min and acetate 43[30] (231 mg, 0.901 mmol) in
THF (1 mL) was added. The mixture was slowly warmed up to 0 °C over 1
h and diluted with saturated NH4Cl. The resulting mixture was extracted
with EtOAc twice and the combined extracts were washed with brine, dried
over MgSO4, and concentrated. The residue was passed through a short
column of silica gel (hexane/EtOAc 10:1) to afford 44. TBAF (1.0 M in THF,
1.80 mL, 1.80 mmol) was added to a solution of 44 in THF (2 mL) and the
solution was stirred at 40–50 °C for 1 h and diluted with saturated NH4Cl.
The product was extracted with EtOAc twice and the combined extracts
were washed with brine, dried over MgSO4, and concentrated to leave a
residue, which was purified by chromatography on silica gel
(hexane/EtOAc 5:1) to afford 45 (109 mg, 84% yield from 43): liquid; Rf
0.36 (hexane/EtOAc 2:1); 1H NMR (300 MHz, CDCl3) δ 1.26 (br s, 1 H),
1.53–1.63 (m, 1 H), 2.87 (dt, J = 13.5, 7.8 Hz, 1 H), 3.80 (dt, J = 1.2, 7.8
Hz, 1 H), 4.94 (q, J = 6.0 Hz, 1 H), 5.94–6.01 (m, 2 H), 7.18–7.35 (m, 5 H).
The 1H NMR spectrum was consistent with that reported.[31]
953, 757 cm–1 1H NMR (400 MHz, CDCl3) δ 0.50–0.62 (m, 1 H), 0.62–
;
1.89 (m, 21 H), 0.75 (s, 3 H), 0.84 (s, 3 H), 1.08 (s, 9 H), 3.63 (t, J = 10.8
Hz, 1 H), 4.86–4.95 (m, 1 H), 7.12–7.27 (m, 6 H), 7.27–7.48 (m, 10 H),
7.63–7.72 (m, 4 H); 13C–APT NMR (75 MHz, CDCl3) δ 11.5 (+), 11.8 (+),
19.4 (–), 20.4 (–), 23.5 (–), 27.1 (+), 27.6 (d, J = 5 Hz) (–), 28.0 (–), 30.8
(–), 31.4 (–), 32.3 (–), 34.2 (–), 35.5 (+), 35.8 (–), 37.0 (–), 39.2 (+), 43.8
(–), 50.4 (+), 54.2 (+), 77.7 (d, J = 6 Hz) (+), 82.6 (+), 120.2 (d, J = 3 Hz)
(+), 125.2 (+), 127.41 (+), 129.47 (+), 129.53 (+), 129.8 (+), 134.5 (–),
135.0 (–), 136.0 (+), 136.1 (+), 150.7 (d, J = 7 Hz) (–); HRMS (FAB+): m/z
calcd for C47H59O5PSiNa [(M+Na)+] 785.3767, found 785.3783.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801596
European Journal of Organic Chemistry
FULL PAPER
A mixture of allylic alcohol 45 (109 mg, 0.680 mmol) and 10% Pd/C (4 mg)
in EtOAc (3 mL) was stirred under hydrogen at rt for 4 h and filtered through
a pad of Celite. The filtrate was concentrated to give a residue, which was
purified by chromatography on silica gel (hexane/EtOAc 3:1) to afford cis
alcohol 46 (66 mg, 60% yield) and the corresponding ketone (33 mg, 30%
yield). Alcohol 46: liquid; Rf 0.38 (hexane/EtOAc 2:1); 1H NMR (300 MHz,
CDCl3) δ 1.54 (br s, 1 H), 1.59–1.72 (m, 1 H), 1.76–2.01 (m, 3 H), 2.02–
2.10 (m, 1 H), 2.48 (ddd, J = 13.8, 8.5, 6.3 Hz, 1 H), 2.98–3.12 (m, 1 H),
4.41–4.51 (m, 1 H), 7.16–7.40 (m, 5 H). The 1H NMR spectrum was
consistent with that reported.[32]
3. Substitution of phosphates with Ar2CHLi
General procedures for the substitution of phosphates with
a
diarylmethyl lithium: To an ice-cold solution of a diarylmethane (3.2–3.7
equiv) in THF was added a solution of nBuLi (3 equiv) in hexane dropwise.
The solution was stirred at 0 °C–rt for 15 min and cooled to –15 °C–0 °C.
Phosphate (1 equiv) in THF was added to the solution dropwise. The
solution was either stirred at –15 °C for a specific period of time (usually
15 min) or warmed to 0 °C over 15–30 min, and diluted with saturated
NH4Cl. The resulting mixture was extracted with EtOAc several times. The
combined extracts were washed with brine, dried over MgSO4, and
concentrated. The crude product was purified by chromatography on silica
gel.
According to the general procedure for the phosphorylation of an alcohol,
a mixture of alcohol 46 (66 mg, 0.407 mmol), diphenyl chlorophosphate
(0.087 mL, 0.656 mmol), and N-methylimidazole (0.064 mL, 0.812 mmol)
in CH2Cl2 (1.5 mL) was stirred at rt overnight, and Me2N(CH2)3NH2
(excess) was added to the solution. After 10 min at rt, saturated NaHCO3
was added and the resulting mixture was extracted with EtOAc twice. The
combined extracts were dried over MgSO4 and concentrated to leave a
residue, which was purified by chromatography on silica gel
(hexane/EtOAc 7:1) to afford 31 (110 mg, 68% yield): liquid; Rf 0.48
(hexane/EtOAc 2:1); IR (neat) 1591, 1490, 1192, 953, 756 cm–1; 1H NMR
(300 MHz, CDCl3) δ 1.75–2.16 (m, 5 H), 2.47–2.62 (m, 1 H), 2.97–3.12 (m,
1 H), 5.16–5.26 (m, 1 H), 7.12–7.37 (m, 15 H); 13C–APT NMR (75 MHz,
CDCl3) δ 32.7 (–), 34.5 (–) (d, J = 6 Hz), 41.7 (–) (d, J = 6 Hz), 43.7 (+),
82.4 (+) (d, J = 7 Hz), 120.1 (+) (d, J = 5 Hz), 125.3 (+), 126.1 (+), 127.1
(+), 128.4 (+), 129.7 (+), 144.7 (–), 150.5 (–) (d, J = 8 Hz); HRMS (FAB+):
m/z calcd for C23H24O4P [(M+H)+] 389.1412, found 389.1412.
Propane-1,1-diyldibenzene (11): According to the general procedure for
the substitution, phosphate 9a (28 mg, 0.097 mmol) in THF (0.5 mL) was
added to a solution of Ph2CH2 (54 mg, 0.320 mmol) and nBuLi (1.60 M in
hexane, 0.19 mL, 0.304 mmol) in THF (0.5 mL) at –15 °C and the solution
was stirred at –15 °C for 15 min to afford a mixture of 11 and 10 in 92:8 by
1H NMR spectroscopy. The major product 11 (17 mg, 89% yield) was
isolated by chromatography on silica gel (hexane): liquid; Rf 0.73
(hexane/EtOAc 2:1); IR (neat) 1600, 1493, 1450, 699 cm–1; 1H NMR (400
MHz, CDCl3) δ 0.89 (t, J = 7.3 Hz, 3 H), 2.07 (dq, J = 7.8, 7.3 Hz, 2 H),
3.79 (t, J = 7.8 Hz, 1 H), 7.14–7.30 (m, 10 H); 13C–APT NMR (100 MHz,
CDCl3) δ 12.9 (+), 28.7 (–), 53.3 (+), 126.1 (+), 128.0 (+), 128.4 (+), 145.2
(–). The 1H and 13C NMR spectra were consistent with those reported.[35,36]
(2-Methylbutane-1,1,4-triyl)tribenzene (10): According to the general
procedure for the substitution, phosphate 9b (77 mg, 0.201 mmol) in THF
(1 mL) was added to a solution of Ph2CH2 (113 mg, 0.672 mmol) and nBuLi
(1.60 M in hexane, 0.37 mL, 0.592 mmol) in THF (1 mL) at –15 °C, and
the solution was stirred at –15 °C for 15 min to afford a 71:29 mixture (68
mg) of 10 and (Ph2CH)2 after chromatography on silica gel
(hexane/EtOAc): 54 mg, 89% yield by 1H NMR. Analytical sample of 10
was obtained by Kugelrohr distillation (ca. 175 °C/5 mmHg): liquid; Rf 0.90
(hexane/EtOAc 2:1); IR (neat) 1599, 1494, 1451, 699 cm–1; 1H NMR (300
MHz, CDCl3) δ 0.92 (t, J = 6.6 Hz, 3 H), 1.23–1.41 (m, 1 H), 1.68–1.80 (m,
1 H), 2.30–2.43 (m, 1 H), 2.52 (ddd, J = 13.5, 9.9, 7.5 Hz, 1 H), 2.75 (ddd,
J = 13.5, 10.2, 4.5 Hz, 1 H), 3.55 (d, J = 11.1 Hz, 1 H), 6.98–7.27 (m, 15
H); 13C–APT NMR (75 MHz, CDCl3) δ 18.2 (+), 33.1 (–), 35.8 (+), 36.7 (–),
59.3 (+), 125.7 (+), 126.0 (+), 126.1 (+), 128.10 (+), 128.13 (+), 128.3 (+),
128.48 (+), 128.50 (+), 128.52 (+), 142.6 (–), 144.5 (–), 144.8 (–); HRMS
(EI+): m/z calcd for C23H24 [M+] 300.1878, found 300.1876.
Diphenyl [(1R*,3R*)-3-phenylcyclopentyl] phosphate (33): According
to the procedure,[33] acetate 47 (299 mg, 2.10 mmol) in THF (1 mL) was
added to a mixture of PhMgCl (0.77 M in THF, 7.50 mL, 5.78 mmol) and
CuCN (57 mg, 0.64 mmol) in THF (5 mL) at –20 °C. The mixture was slowly
warmed up to 0 °C over 3 h and diluted with saturated NH4Cl. The resulting
mixture was extracted with EtOAc twice and the combined extracts were
washed with brine, dried over MgSO4, and concentrated. The residue was
purified by chromatography on silica gel (hexane/EtOAc 5:1) to afford 48
(325 mg, 95% yield): liquid; Rf 0.24 (hexane/EtOAc 2:1); 1H NMR (300
MHz, CDCl3) δ 1.50 (d, J = 6.9 Hz, 1 H), 2.11 (ddd, J = 14.2, 7.2, 5.7 Hz,
1 H), 2.30 (ddd, J = 14.2, 7.8, 2.7 Hz, 1 H), 4.11–4.20 (m, 1 H), 5.02–5.61
(m, 1 H), 6.00–6.08 (m, 2 H), 7.11–7.33 (m, 5 H). The 1H NMR spectrum
was consistent with that reported.[34]
A mixture of allylic alcohol 48 (325 mg, 2.03 mmol) and 10% Pd/C (11 mg)
in EtOAc (6 mL) was stirred under hydrogen at rt for 4 h and filtered through
a pad of Celite. The filtrate was concentrated to give a residue, which was
passed through a pad of Celite to afford trans alcohol 49: 1H NMR (300
MHz, CDCl3) δ 1.44 (br s, 1 H), 1.56–1.75 (m, 2 H), 1.79–1.90 (m, 1 H),
2.04–2.14 (m, 1 H), 2.16–2.32 (m, 2 H), 3.33–3.47 (m, 1 H), 4.49–4.60 (m,
1 H), 7.16–7.42 (m, 5 H). The 1H NMR spectrum was consistent with that
reported.[32] According to the general procedure for the phosphorylation of
an alcohol, a mixture of the above alcohol, diphenyl chlorophosphate (0.43
mL, 3.24 mmol), and N-methylimidazole (0.32 mL, 4.06 mmol) in CH2Cl2
(7 mL) was stirred at rt overnight, and Me2N(CH2)3NH2 (excess) was added
to the solution. After 10 min at rt, saturated NaHCO3 was added and the
product was purified by chromatography on silica gel (hexane/EtOAc 7:1)
to afford 33 (610 mg, 76% yield from 48): liquid; Rf 0.52 (hexane/EtOAc
2:1); IR (neat) 1591, 1490, 1192, 953 cm–1; 1H NMR (300 MHz, CDCl3) δ
1.54–1.72 (m, 1 H), 1.76–2.42 (m, 5 H), 3.22–3.42 (m, 1 H), 5.20–5.58 (m,
1 H), 7.10–7.38 (m, 15 H); 13C–APT NMR (75 MHz, CDCl3) δ 31.9 (–), 33.8
(–) (d, J = 5 Hz), 42.4 (–) (d, J = 5 Hz), 42.6 (+), 83.1 (+) (d, J = 7 Hz),
120.1 (+) (d, J = 5 Hz), 125.3 (+), 126.2 (+), 126.9 (+), 128.4 (+), 129.8 (+),
144.4 (–), 150.6 (–) (d, J = 7 Hz); HRMS (FAB+): m/z calcd for C23H24O4P
[(M+H)+] 389.1412, found 389.1424.
(2-Methylpropane-1,1-diyl)dibenzene (13a): According to the general
procedure for the substitution, phosphate 12a (30 mg, 0.102 mmol) in THF
(0.5 mL) was added to a solution of Ph2CH2 (56 mg, 0.33 mmol) and nBuLi
(1.60 M in hexane, 0.19 mL, 0.307 mmol) in THF (0.5 mL) at –15 °C, and
the solution was stirred at –15 °C for 15 min to afford 13a (21 mg, 99%
yield): liquid; Rf 0.85 (hexane/EtOAc 1:1); IR (neat) 1598, 1493, 1451, 702
cm–1 1H NMR (400 MHz, CDCl3) δ 0.87 (d, J = 6.5 Hz, 6 H), 2.49 (d of
;
sept., J = 10.8, 6.5 Hz, 1 H), 3.40 (d, J = 10.8 Hz, 1 H), 7.13 (t, J = 7.1 Hz,
2 H), 7.22–7.31 (m, 8 H); 13C–APT NMR (100 MHz, CDCl3) δ 21.9 (+), 31.9
(+), 61.0 (+), 126.0 (+), 128.1 (+), 128.5 (+), 145.0 (–). The 1H and 13C
NMR spectra were consistent with those reported.[37]
(2-Ethylbutane-1,1-diyl)dibenzene (13b): According to the general
procedure for the substitution, phosphate 12b (64 mg, 0.199 mmol) in THF
(1 mL) was added to a solution of Ph2CH2 (108 mg, 0.639 mmol) and nBuLi
(1.60 M in hexane, 0.37 mL, 0.595 mmol) in THF (1 mL) at –15 °C, and
the solution was stirred at –15 °C for 15 min to afford 13b (47 mg, 99%
yield): solids; mp 32–33 °C; Rf 0.85 (hexane/EtOAc 1:1); IR (nujol) 1598,
1493, 1451, 1378, 704 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.79 (t, J = 7.4
Hz, 6 H), 1.16–1.28 (m, 2 H), 1.33–1.44 (m, 2 H), 2.18–2.28 (m, 1 H), 3.69
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801596
European Journal of Organic Chemistry
FULL PAPER
(d, J = 11.2 Hz, 1 H), 7.13 (t, J = 7.2 Hz, 2 H), 7.24 (dd, J = 7.8, 7.2 Hz, 4
H), 7.29 (d, J = 7.8 Hz, 4 H); 13C–APT NMR (100 MHz, CDCl3) δ 10.0 (+),
22.0 (–), 42.9 (+), 55.8 (+), 126.0 (+), 128.2 (+), 128.5 (+), 144.9 (–); HRMS
(EI+): m/z calcd for C18H22 [M+] 238.1722, found 238.1723.
slowly to 0 °C over 30 min to afford 15a (38 mg, 89% yield): liquid; Rf 0.23
(hexane/EtOAc 29:1); [α]D21 +7 (c 0.95, CHCl3); IR (neat) 1494, 1255, 1094,
835 cm–1; 1H NMR (400 MHz, CDCl3) δ –0.03 (s, 3 H), –0.02 (s, 3 H), 0.84
(s, 9 H), 0.84 (d, J = 6.6 Hz, 3 H), 0.92–1.04 (m, 1 H), 1.37–1.50 (m, 2 H),
1.57–1.68 (m, 1 H), 2.26–2.42 (m, 1 H), 3.49 (t, J = 6.6 Hz, 2 H), 3.51 (d,
J = 10.8 Hz, 1 H), 7.10–7.17 (m, 2 H), 7.21–7.29 (m, 8 H); 13C NMR (100
MHz, CDCl3) δ –5.2 (+), 18.3 (+), 18.4 (–), 26.0 (+), 30.3 (–), 31.1 (–), 36.4
(+), 59.5 (+), 63.5 (–), 125.99 (+), 126.02 (+), 128.1 (+), 128.2 (+), 128.46
(+), 128.52 (+), 144.7 (–), 144.9 (–); HRMS (FAB+): m/z calcd for
C24H36OSiNa [(M+Na)+] 391.2433, found 391.2441.
(2-Isopropyl-3-methylbutane-1,1-diyl)dibenzene (13c): According to
the general procedure for the substitution, phosphate 12c (68 mg, 0.195
mmol) in THF (1 mL) was added to a solution of Ph2CH2 (121 mg, 0.719
mmol) and nBuLi (1.60 M in hexane, 0.37 mL, 0.592 mmol) in THF (1 mL)
at –15 °C and the solution was stirred at –15 °C for 15 min to afford 13c
(45 mg, 85% yield): solids; mp 91–92 °C; Rf 0.90 (hexane/EtOAc 4:1); IR
(nujol) 1596, 1490, 1450, 1368, 1074 cm–1
;
1H NMR (400 MHz, CDCl3) δ
(R)-4-Methyl-5,5-diphenylpentan-1-ol (16a): A solution of 15a (38 mg,
0.99 mmol) and PPTS (35 mg, 0.14 mmol) in MeOH (0.3 mL) was stirred
at rt for 3 h and diluted with saturated NaHCO3. The resulting mixture was
extracted with EtOAc three times. The combined extracts were washed
with brine, dried over MgSO4, and concentrated to leave a residue, which
was purified by chromatography on silica gel (hexane/EtOAc 3:1) to afford
alcohol 16a (19 mg, 88% yield): 97.3% ee by HPLC (Chiralpak AD-H,
hexane/iPrOH = 99:1, 1.0 mL/min, tR/min = 22.91 (R-isomer, major), 25.43
0.75 (d, J = 7.1 Hz, 6 H), 0.92 (d, J = 7.1 Hz, 6 H), 1.81 (d of sept., J = 1.8,
7.1 Hz, 2 H), 2.33 (dt, J = 12.0, 1.8 Hz, 1 H), 3.95 (d, J = 12.0 Hz, 1 H),
7.09 (t, J = 7.4 Hz, 2 H), 7.21 (t, J = 7.4 Hz, 4 H), 7.35 (t, J = 7.4 Hz, 4 H);
13C–APT NMR (100 MHz, CDCl3) δ 21.0 (+), 21.2 (+), 27.7 (+), 50.7 (+),
54.0 (+), 125.9 (+), 128.4 (+), 145.9 (–); HRMS (EI+): m/z calcd for C20H26
[M+] 266.2035, found 266.2036.
20
(S-isomer, minor); liquid; Rf 0.16 (hexane/EtOAc 5:1); [α]D +4 (c 1.00,
9-Isopropyl-9H-xanthene (13e): According to the general procedure for
the substitution, phosphate 12a (200 mg, 0.684 mmol) in THF (0.5 mL)
was added to an ice-cold solution of xanthene (399 mg, 1.29 mmol) and
nBuLi (1.57 M in hexane, 1.30 mL, 2.04 mmol) in THF (1.5 mL), and the
solution was stirred at 0 °C for 30 min to afford 13e (124 mg, 81% yield):
mp 54–56 °C; Rf 0.55 (hexane); IR (neat) 1477, 1457, 1254, 750 cm–1; 1H
NMR (300 MHz, CDCl3) δ 0.82 (d, J = 6.9 Hz, 6 H), 1.97 (d of sept., J =
4.4, 6.9 Hz, 1 H), 3.81 (d, J = 4.4 Hz, 1 H), 7.06–7.16 (m, 4 H), 7.18–7.30
(m, 4 H); 13C–APT NMR (75 MHz, CDCl3) δ 19.0 (+), 37.9 (+), 45.9 (+),
116.2 (+), 122.8 (+), 124.5 (–), 127.5 (+), 129.4 (+), 153.0 (–); HRMS
(FAB+): m/z calcd for C16H16O [M+] 224.1201, found 224.1190.
CHCl3); IR (neat) 3364, 1597, 1493, 1450, 1218, 756, 704 cm–1; 1H NMR
(400 MHz, CDCl3) δ 0.86 (d, J = 6.8 Hz, 3 H), 1.00–1.15 (m, 2 H), 1.39–
1.56 (m, 2 H), 1.62–1.74 (m, 1 H), 2.32–2.44 (m, 1 H), 3.47–3.59 (m, 3 H),
7.11–7.16 (m, 2 H), 7.22–7.30 (m, 8 H); 13C NMR (100 MHz, CDCl3) δ 18.3
(+), 30.1 (–), 30.9 (–), 36.3 (+), 59.4 (+), 63.2 (–), 126.0 (+), 126.1 (+),
128.0 (+), 128.1 (+), 128.5 (+), 128.6 (+), 144.6 (–), 144.7 (–); HRMS
(FAB+): m/z calcd for C18H22ONa [(M+Na)+] 277.1568 , found 277.1570.
(R,E)-4-Methyl-5,5-diphenylpent-2-en-1-ol (18a): According to the
procedure,[8] allylic phosphate 17a (97.9% ee, 410 mg, 1.16 mmol) in THF
(5 mL) was added to an ice-cold solution of Ph2CH2 (626 mg, 3.72 mmol)
and nBuLi (1.55 M in hexane, 2.20 mL, 3.41 mmol) in THF (7 mL), and the
solution was stirred at 0 °C for 20 min to afford the TBS ether of 18a (360
mg, 85%). To an ice-cold solution of this product (360 mg, 0.982 mmol) in
THF (6 mL) was added TBAF (1.0 M in THF, 1.74 mL, 1.74 mmol). The
solution was stirred at 0 °C for 3 h and diluted with saturated NH4Cl. The
resulting mixture was extracted with EtOAc three times. The combined
extracts were dried over MgSO4 and concentrated to leave a residue,
which was purified by chromatography on silica gel (hexane/EtOAc 3:1) to
afford alcohol 18a (230 mg, 93% yield): liquid; Rf 0.25 (hexane/EtOAc 3:1);
[α]D21 +20 (c 1.04, CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.91 (t, J = 5.8 Hz,
1 H), 0.98 (d, J = 6.4 Hz, 3 H), 3.01–3.13 (m, 1 H), 3.62 (d, J = 10.8 Hz, 1
H), 3.86–3.98 (m, 2 H), 5.48–5.59 (m, 2 H), 7.09–7.32 (m, 10 H); 13C NMR
(100 MHz, CDCl3) δ 19.6, 40.3, 58.7, 63.7, 126.1, 126.3, 128.1, 128.3,
128.45, 128.55, 128.9, 137.3, 143.9, 144.0. The 1H and 13C NMR spectra
were identical with those reported.[8]
9-(Pentan-3-yl)-9H-xanthene (13f): According to the general procedure
for the substitution, phosphate 12b (271 mg, 0.846 mmol) in THF (0.5 mL)
was added to an ice-cold solution of xanthene (493 mg, 2.71 mmol) and
nBuLi (1.57 M in hexane, 1.60 mL, 2.51 mmol) in THF (1.5 mL), and the
solution was stirred at 0 °C for 30 min to afford 13f (168 mg, 79% yield):
liquid; Rf 0.55 (hexane only); IR (neat) 1478, 1457, 1256, 749 cm–1 1H
;
NMR (300 MHz, CDCl3) δ 0.88 (d, J = 7.2 Hz, 6 H), 1.03–1.18 (m, 2 H),
1.22–1.37 (m, 2 H), 1.42 (d of quint., J = 3.9, 6.6 Hz, 1 H), 4.07 (d, J = 3.6
Hz, 1 H), 7.01–7.11 (m, 4 H), 7.12–7.24 (m, 4 H); 13C–APT NMR (75 MHz,
CDCl3) δ 12.1 (+), 22.0 (–), 40.6 (+), 52.3 (+), 116.2 (+), 123.0 (+), 124.9
(+), 127.4 (+), 129.2 (+), 153.3 (–); HRMS (FAB+): m/z calcd for C18H20
[M+] 252.1514, found 252.1510.
O
9-(2,4-Dimethylpentan-3-yl)-9H-xanthene (13g): According to the
general procedure for the substitution, phosphate 12c (219 mg, 0.629
mmol) in THF (0.5 mL) was added to an ice-cold solution of xanthene (354
mg, 1.94 mmol) and nBuLi (1.57 M in hexane, 1.20 mL, 1.88 mmol) in THF
(2.5 mL), and the solution was stirred at 0 °C for 30 min to give a mixture
(50 mg) of 13g and the xanthene dimer[38] in a 77:33 ratio by 1H NMR
analysis (20% yield), and preparative HPLC afforded analytical sample of
(R)-4-Methyl-5,5-diphenylpentan-1-ol (16a): A mixture of allylic alcohol
18a (35 mg, 0.14 mmol) and 10% Pd/C (5 mg) in EtOH (0.7 mL) was stirred
under hydrogen at rt for 1.5 h, and filtered through a pad of silica gel. The
filtrate was concentrated to give a residue, which was purified by
chromatography on silica gel (toluene/EtOAc 3:1) to afford alkyl alcohol
16a (23 mg, 65% yield): 94.0% ee by HPLC (Chiralpak AD-H,
hexane/iPrOH = 99:1, 1.0 mL/min, 35 °C, tR/min = 23.16 (R-isomer, major),
25.42 (S-isomer, minor); liquid; Rf 0.33 (hexane/EtOAc 3:1). The 1H NMR
spectrum was consistent with that obtained above.
13g: liquid; Rf 0.59 (hexane); IR (neat) 1480, 1457, 1255, 755 cm–1 1H
;
NMR (300 MHz, CDCl3) δ 0.64 (d, J = 6.9 Hz, 3 H), 1.01 (d, J = 6.9 Hz, 3
H), 1.35 (dt, J = 2.6, 5.6 Hz, 1 H), 1.90 (d of sept., J = 5.6, 6.9 Hz, 2 H),
4.36 (d, J = 2.6 Hz, 1 H), 7.01–7.10 (m, 4 H), 7.16–7.25 (m, 4 H); 13C–APT
NMR (75 MHz, CDCl3) δ 20.4 (+), 24.6 (+), 27.2 (+), 39.5 (+), 61.6 (+),
116.3 (+), 123.0 (+), 125.0 (–), 127.5 (+), 129.2 (+), 153.0 (–); HRMS
(FAB+): m/z calcd for C20H24OCs [(M+Cs)+] 413.0881, found 413.0884.
(R)-[(4-Benzhydrylhexyl)oxy](tert-butyl)dimethylsilane
(15b):
According to the general procedure for the substitution, phosphate 14b
(96.2% ee, 57 mg, 0.12 mmol) in THF (0.5 mL) was added to a solution of
Ph2CH2 (0.066 mL, 0.39 mmol) and nBuLi (1.55 M in hexane, 0.25 mL,
0.39 mmol) in THF (1.5 mL) at –15 °C, and the solution was warmed slowly
(R)-tert-Butyldimethyl[(4-methyl-5,5-diphenylpentyl)oxy]silane (15a):
According to the general procedure for the substitution, phosphate 14a
(97.5% ee, 50 mg, 0.11 mmol) in THF (0.4 mL) was added dropwise to a
solution of Ph2CH2 (60 mg, 0.36 mmol) in THF (0.7 mL) and nBuLi (1.55
M in hexane, 0.21 mL, 0.32 mmol) at –15 °C, and the solution was warmed
to 0 °C over 15 min to give 15b (43 mg, 92% yield): liquid; Rf 0.31 (hexane);
22
[α]D +9 (c 1.15, CHCl3); IR (neat) 1255, 1097, 836, 703 cm–1 1H NMR
;
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801596
European Journal of Organic Chemistry
FULL PAPER
(400 MHz, CDCl3) δ –0.01 (s, 3 H), 0.00 (s, 3 H), 0.82 (t, J = 7.4 Hz, 3 H),
0.86 (s, 9 H), 1.15–1.31 (m, 2 H), 1.33–1.61 (m, 4 H), 2.32 (dtt, J = 11.2,
6.4, 3.2 Hz, 1 H), 3.47 (t, J = 6.6 Hz, 2 H), 3.71 (d, J = 11.2 Hz, 1 H), 7.11–
7.17 (m, 2 H), 7.22–7.33 (m, 8 H); 13C–APT NMR (100 MHz, CDCl3) δ –
5.2 (+), 9.8 (+), 18.4 (–), 22.6 (–), 25.7 (–), 26.0 (+), 29.2 (–), 41.5 (+), 56.0
(+), 63.6 (–), 126.0 (+), 128.2 (+), 128.5 (+), 144.7 (–), 144.8 (–); HRMS
(FAB+): m/z calcd for C25H39OSi [(M+H)+] 383.2770, found 383.2764.
0.53 mmol) in THF (1.5 mL) at –15 °C, and the solution was warmed slowly
to 0 °C over 30 min to afford 15c (68 mg, 94% yield): liquid; Rf 0.37
(hexane); [α]D21 +31 (c 1.23, CHCl3); IR (neat) 1255, 1097, 836, 703 cm–1
;
1H NMR (400 MHz, CDCl3) δ 0.00 (s, 6 H), 0.79 (d, J = 6.8 Hz, 3 H), 0.88
(s, 9 H), 0.97 (d, J = 6.8 Hz, 3 H), 1.07–1.21 (m, 2 H), 1.29–1.49 (m, 2 H),
1.79 (d of sept., J = 2.4, 6.8 Hz, 1 H), 2.17–2.36 (dm, J = 11.6 Hz, 1 H),
3.36 (t, J = 6.0 Hz, 2 H), 3.76 (d, J = 11.6 Hz, 1 H), 7.14 (t, J = 7.6 Hz, 1
H), 7.16 (t, J = 7.6 Hz, 1 H), 7.25 (t, J = 7.6 Hz, 2 H), 7.28 (t, J = 7.6 Hz, 2
H), 7.35 (d, J = 7.6 Hz, 4 H); 13C–APT NMR (100 MHz, CDCl3) δ –5.2 (+),
15.9 (+), 18.4 (–), 22.0 (+), 24.3 (–), 26.0 (+), 28.7 (+), 33.8 (–), 46.9 (+),
57.1 (+), 63.6 (–), 126.0 (+), 126.1 (+), 128.1 (+), 128.43 (+), 128.45 (+),
128.5 (+), 144.9 (–), 145.0 (–); HRMS (FAB+): m/z calcd for C26H41OSi
[(M+H)+] 397.2927, found 397.2929.
(R)-4-Benzhydrylhexan-1-ol (16b): According to the desilylation to afford
18a, a solution of 15b (43 mg, 0.11 mmol) and PPTS (50 mg, 0.20 mmol)
in MeOH (2 mL) was stirred at rt for 2 h to produce alcohol 16b (27 mg,
91% yield): 96.1% ee by HPLC (Chiralpak IC, hexane/iPrOH = 99:1, 1.0
mL/min, 35 °C, tR/min = 24.82 (S-isomer, minor), 26.22 (R-isomer, major);
26
liquid; Rf 0.33 (hexane/EtOAc 9:1); [α]D +8 (c 1.13, CHCl3); IR (neat)
3356, 1493, 1451, 909 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.83 (t, J = 7.4
Hz, 3 H), 1.18–1.33 (m, 3 H), 1.33–1.51 (m, 3 H), 1.53–1.65 (m, 1 H), 2.33
(dtt, J = 11.2, 6.8, 3.4 Hz, 1 H), 3.43–3.54 (m, 2 H), 3.71 (d, J = 11.2 Hz, 1
H), 7.15 (tq, J = 7.2, 1.6 Hz, 2 H), 7.23–7.33 (m, 8 H); 13C–APT NMR (100
MHz, CDCl3) δ 9.9 (+), 22.7 (–), 25.7 (–), 29.2 (–), 41.5 (+), 56.1 (+), 63.3
(–), 126.05 (+), 126.12 (+), 128.1 (+), 128.5 (+), 128.6 (+), 144.6 (–); HRMS
(FAB+): m/z calcd for C19H24ONa [(M+Na)+] 291.1725, found 291.1729.
(S)-4-Benzhydryl-5-methylhexan-1-ol (16c): According to the
desilylation to afford 18a, a solution of 15c (68 mg, 0.17 mmol) and PPTS
(54 mg, 0.21 mmol) in MeOH (2 mL) was stirred at rt for 2 h to afford alcohol
16c (39 mg, 82% yield): 96.2% ee by HPLC (Chiralpak AD-H,
hexane/iPrOH = 97:3, 1.0 mL/min, 35 °C, tR/min = 9.83 (S-isomer, major),
11.61 (R-isomer, minor); solids, mp 67–68 °C; Rf 0.32 (hexane/EtOAc 3:1);
[α]D22 +54 (c 0.98, CHCl3); IR (neat) 3375, 1494, 974, 753 cm–1 1H NMR
;
(400 MHz, CDCl3) δ 0.76 (d, J = 7.1 Hz, 3 H), 0.94 (d, J = 7.1 Hz, 3 H),
1.00–1.22 (m, 2 H), 1.31–1.47 (m, 2 H), 1.78 (d of sept., J = 2.8, 7.1 Hz, 2
H), 2.17 (ddt, J = 11.2, 2.8, 4.6 Hz, 1 H), 3.34 (t, J = 6.4 Hz, 2 H), 3.73 (d,
J = 11.2 Hz, 1 H), 7.11–7.18 (m, 2 H), 7.21–7.36 (m, 8 H); 13C–APT NMR
(100 MHz, CDCl3) δ 15.8 (+), 22.0 (+), 23.9 (–), 28.7 (+), 33.6 (–), 46.8 (+),
57.0 (+), 63.2 (–), 126.1 (+), 126.2 (+), 128.1 (+), 128.47 (+), 128.51 (+),
128.6 (+), 144.7 (–), 144.8 (–); HRMS (FAB+): m/z calcd for C20H26OSiNa
[(M+Na)+] 305.1881, found 305.1881.
(R,E)-4-Benzhydrylhex-2-en-1-ol (18b): According to the procedure,[8]
allylic phosphate 17b (96.7% ee, 258 mg, 0.704 mmol) in THF (2 mL) was
added to a solution of Ph2CH2 (0.375 mL, 2.25 mmol) and nBuLi (1.55 M
in hexane, 1.32 mL, 2.05 mmol) in THF (5 mL) –15 °C. The solution was
warmed to 0 °C over 30 min to afford a mixture of the TBS ethers of 18b
and 19b (the regioisomer). According to the desilylation to afford 18a, a
solution of the above mixture and PPTS (181 mg, 0.720 mmol) in MeOH
(5 mL) was stirred at rt for 2 h, and chromatography of the products on
silica gel (hexane/EtOAc 3:1) gave alcohol 18b (111 mg, 73% yield from
17b) and the regioisomer 19b (11 mg, 6% yield from 17b). 18b: liquid; Rf
0.30 (hexane/EtOAc 3:1); IR (neat) 3357, 1494, 1451, 703 cm–1; 1H NMR
(400 MHz, CDCl3) δ 0.88 (dt, J = 3.2, 7.2 Hz, 3 H), 1.12–1.34 (m, 2 H),
1.48–1.60 (m, 1 H), 2.84 (ddt, J = 10.6, 8.8, 3.0 Hz, 1 H), 3.78 (dd, J = 10.6,
3.0 Hz, 1 H), 3.86 (dd, J = 12.8, 5.8 Hz, 1 H), 3.92 (dd, J =12.8, 5.8 Hz, 1
H), 5.36 (ddt, J = 15.5, 8.8, 1.2 Hz, 1 H), 5.52 (ddt, J = 15.5, 2.2, 5.8 Hz, 1
H), 7.10–7.38 (m, 10 H); 13C–APT NMR (100 MHz, CDCl3) δ 11.7 (+), 25.9
(–), 48.2 (+), 57.2 (+), 63.4 (–), 126.0 (+), 126.2 (+), 128.1 (+), 128.2 (+),
128.5 (+), 131.2 (+), 135.1 (+), 143.8 (–), 144.1 (–); HRMS (EI+): m/z calcd
(R,E)-[(4-Benzhydryl-5-methylhex-2-en-1-yl)oxy](tert-
butyl)dimethylsilane (18c): According to the procedure,[8] allylic
phosphate 17c (96.5% ee, 197 mg, 0.518 mmol) in THF (1 mL) was added
to a solution of Ph2CH2 (0.276 mL, 1.64 mmol) and nBuLi (1.55 M in
hexane, 0.971 mL, 1.51 mmol) in THF (4 mL) at –15 °C, and the solution
was warmed slowly to 0 °C over 30 min to give a mixture of the TBS ethers
of 18c and 19c (the regioisomer). According to the desilylation to afford
18a, a solution of the above mixture and PPTS (135 mg, 0.537 mmol) in
MeOH (5 mL) was stirred at rt for 2 h and the products were purified by
chromatography on silica gel (hexane/EtOAc 3:1) to produce alcohol 18c
(35 mg, 31% yield from 17c) and the regioisomer 19c (60 mg, 41% yield
from 17c). 18c: liquid; Rf 0.31 (hexane/EtOAc 3:1); IR (neat) 3375, 1494,
974, 703 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.83 (d, J = 6.8 Hz, 3 H), 0.87
(d, J = 6.8 Hz, 3 H), 1.64 (br s, 1 H) 1.72 (d of sept., J = 3.0, 6.8 Hz, 1 H),
2.86 (ddd, J = 11.4, 9.4, 3.0 Hz, 1 H), 3.85 (dd, J =12.4, 6.0 Hz, 1 H), 3.89
(dd, J = 12.4, 6.0 Hz, 1 H), 3.92 (d, J = 11.4 Hz, 1 H), 5.34 (dd, J = 15.4,
9.2 Hz, 1 H), 5.46 (dd, J = 15.4, 6.0 Hz, 1 H), 7.07–7.37 (m, 10 H); 13C–
APT NMR (100 MHz, CDCl3) δ 15.6 (+), 22.3 (+), 27.9 (+), 52.1 (+), 54.8
(+), 63.6 (–), 126.0 (+), 126.3 (+), 128.1 (+), 128.2 (+), 128.6 (+), 128.7 (+),
131.6 (+), 132.6 (+), 143.7 (–), 144.4 (–); HRMS (FAB+): m/z calcd for
C20H24ONa [(M+Na)+] 303.1725, found 303.1734. 19c: liquid; Rf 0.45
(hexane/EtOAc 3:1); IR (neat) 3398, 1599, 1495, 1032, 702 cm–1; 1H NMR
(400 MHz, CDCl3) δ 0.78 (d, J = 6.8 Hz, 3 H), 0.85 (d, J = 6.8 Hz, 3 H),
1.51 (br s, 1 H), 2.15 (d of oct., J = 1.0, 6.8 Hz, 1 H), 3.05 (ddt, J = 10.8,
3.8, 8.4 Hz, 1 H), 3.33 (dd, J = 10.8, 8.4 Hz, 1 H), 3.54 (dm, J = 10.4 Hz,
1 H), 3.83 (d, J = 10.8 Hz, 1 H), 5.09 (ddd, J = 15.6, 8.4, 1.0 Hz, 1 H), 5.47
(dd, J = 15.6, 6.8 Hz, 1 H), 7.09–7.20 (m, 2 H), 7.20–7.35 (m, 8 H); 13C–
APT NMR (100 MHz, CDCl3) δ 22.3 (+), 22.6 (+), 31.3 (+), 49.6 (+), 53.7
(+), 64.5 (–), 126.1 (+), 126.5 (+), 126.6 (+), 128.0 (+), 128.2 (+), 128.7 (+),
142.9 (+), 143.3 (–); HRMS (FAB+): m/z calcd for C20H24ONa [(M+Na)+]
303.1725, found 303.1727.
for C19H22
O
[M+] 266.1671, found 266.1677. 19b: liquid; Rf 0.40
(hexane/EtOAc 3:1); IR (neat) 3417, 1495, 1032, 702 cm–1; 1H NMR (400
MHz, CDCl3) δ 0.81 (t, J = 7.4 Hz, 3 H), 1.52 (br s, 1 H), 1.92 (quint., J =
7.4 Hz, 2 H), 3.06 (ddt, J = 11.2, 3.6, 8.4 Hz, 1 H), 3.32 (dd, J = 10.6, 8.4
Hz, 1 H), 3.53 (dd, J = 10.6, 3.8 Hz, 1 H), 3.84 (d, J = 11.2 Hz, 1 H), 5.15
(dd, J = 15.4, 8.8 Hz, 1 H), 5.57 (dt, J = 15.4, 6.4 Hz, 1 H), 7.09–7.19 (m,
2 H), 7.20–7.33 (m, 8 H); 13C–APT NMR (100 MHz, CDCl3) δ 13.8 (+), 25.8
(–), 49.1 (+), 53.6 (+), 64.5 (–), 126.1 (+), 126.5 (+), 128.0 (+), 128.3 (+),
128.69 (+), 128.73 (+), 137.2 (+), 143.26 (–), 143.35 (–); HRMS (EI+): m/z
calcd for C19H22O [M+] 266.1671, found 266.1675.
(R)-4-Benzhydrylhexan-1-ol (16b): According to the hydrogenation of
18a, a mixture of allylic alcohol 18b (50 mg, 0.19 mmol) and 10% Pd/C (8
mg) in MeOH (2 mL) was stirred under hydrogen at rt for 3 h to afford
alcohol 16b (41 mg, 79% yield): 95.3% ee by HPLC (Chiralpak IC,
hexane/iPrOH = 99:1, 1.0 mL/min, 35 °C, tR/min = 24.91 (S-isomer, minor),
26.41(R-isomer, major); liquid; Rf 0.43 (hexane/EtOAc 3:1). The 1H NMR
spectrum of 16b was consistent with that obtained from alkyl phosphate
14b.
(S)-[(4-Benzhydryl-5-methylhexyl)oxy](tert-butyl)dimethylsilane
(15c): According to the general procedure for the substitution, phosphate
14c (96.3% ee, 87 mg, 0.18 mmol) in THF (0.5 mL) was added to a solution
of Ph2CH2 (0.097 mL, 0.58 mmol) and nBuLi (1.55 M in hexane, 0.34 mL,
(S)-4-Benzhydryl-5-methylhexan-1-ol (16c): According to the
hydrogenation of 18a, a mixture of allylic alcohol 18c (30 mg, 0.11 mmol)
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10.1002/ejoc.201801596
European Journal of Organic Chemistry
FULL PAPER
and 10% Pd/C (9 mg) in MeOH (2 mL) was stirred under hydrogen at rt for
3 h to produce alcohol 16c (22 mg, 71% yield): 95.7% ee by HPLC
(Chiralpak AD-H, hexane/iPrOH = 97:3, 1.0 mL/min, 35 °C, tR/min = 9.82
(S-isomer, major), 11.59 (R-isomer, minor); liquid; Rf 0.33 (hexane/EtOAc
3:1). The 1H NMR spectrum of 16c was consistent with that obtained from
alkyl phosphate 14c.
mmol) in THF (0.5 mL) was added to a solution of Ph2CH2 (55 mg, 0.33
mmol) and nBuLi (1.61 M in hexane, 0.19 mL, 0.31 mmol) in THF (0.5 mL)
at –15 °C, and the solution was stirred at –15 °C for 3 h to give 25e (22
mg, 82% yield): liquid; Rf 0.47 (hexane); IR (neat) 1597, 1493, 1449, 1032,
745 cm–1 1H NMR (300 MHz, CDCl3) δ 0.84–0.94 (m, 1 H), 0.95 (d, J =
;
6.9 Hz, 3 H), 1.22–1.52 (m, 7 H), 1.60–1.74 (m, 1 H), 2.28–2.41 (m, 1 H),
3.80 (d, J = 11.7 Hz, 1 H), 7.15 (tt, J = 7.0, 1.5 Hz, 2 H), 7.27 (t, J = 7.0 Hz,
4 H), 7.33 (d, J = 7.0 Hz, 4 H); 13C–APT NMR (75 MHz, CDCl3) δ 20.2 (+),
27.1 (–), 30.0 (+), 30.8 (–), 39.0 (+), 55.7 (+), 126.0 (+), 128.1 (+), 128.5
(+), 144.7 (–); HRMS (FAB+): m/z calcd for C20H24 [M+] 264.1878, found
264.1873.
(Cyclohexylmethylene)dibenzene (25a): According to the general
procedure for the substitution, phosphate 24a (67 mg, 0.201 mmol) in THF
(1 mL) was added to a solution of Ph2CH2 (108 mg, 0.640 mmol) and nBuLi
(1.60 M in hexane, 0.38 mL, 0.608 mmol) in THF (1 mL) at –15 °C, and
the solution was stirred at –15 °C for 15 min to afford 25a (45 mg, 88%
yield): solids; mp 46–47 °C; Rf 0.80 (hexane/EtOAc 1:1); IR (nujol) 1597,
[((1R*,3R*)-3-Methylcyclohexyl)methylene]dibenzene (25f): According
to the general procedure for the substitution, phosphate 24f (33 mg, 0.095
mmol) in THF (0.5 mL) was added to a solution of Ph2CH2 (52 mg, 0.31
mmol) and nBuLi (1.61 M in hexane, 0.18 mL, 0.29 mmol) in THF (0.5 mL)
at –15 °C, and the solution was stirred at –15 °C for 4 h to afford 25f (11
mg, 44% yield) and the starting phosphate 24f (9 mg, 27% yield): liquid; Rf
1491, 1032, 701 cm–1 1H NMR (400 MHz, CDCl3) δ 0.78–0.94 (m, 2 H),
;
1.01–1.32 (m, 3 H), 1.59–1.74 (m, 5 H), 2.14 (tq, J = 3.2, 10.8 Hz, 1 H),
3.47 (d, J = 11.0 Hz, 1 H), 7.12 (tt, J = 6.8, 1.8 Hz, 2 H), 7.21–7.29 (m, 8
H); 13C–APT NMR (100 MHz, CDCl3) δ 26.4 (–), 26.6 (–), 32.1 (–), 41.3
(+), 59.6 (+), 125.9 (+), 128.2 (+), 128.4 (+), 144.5 (–); HRMS (EI+): m/z
calcd for C19H22 [M+] 250.1722, found 250.1723. The 1H and 13C NMR
spectra were consistent with that reported.[39]
0.47 (hexane); IR (neat) 1597, 1493, 1450, 745, 702 cm–1 1H NMR (300
;
MHz, CDCl3) δ 0.86 (d, J = 6.9 Hz, 3 H), 1.05–1.64 (m, 8 H), 1.74–1.88 (m,
1 H), 2.42–2.56 (m, 1 H), 3.75 (d, J = 11.7 Hz, 1 H), 7.09–7.17 (m, 2 H),
7.20–7.34 (m, 8 H); 13C–APT NMR (75 MHz, CDCl3) δ 20.6 (+), 20.8 (–),
27.2 (+), 30.1 (–), 33.6 (–), 36.1 (+), 37.4 (–), 56.1 (+), 126.0 (+), 128.08
(+), 128.11 (+), 128.5 (+), 144.6 (–), 144.8 (–); HRMS (FAB+): m/z calcd
for C20H24 [M+] 264.1878, found 264.1878.
[((1r,4r)-4-(tert-Butyl)cyclohexyl)methylene]dibenzene
(25b):
According to the general procedure for the substitution, phosphate 24b (52
mg, 0.134 mmol) in THF (1 mL) was added to a solution of Ph2CH2 (72 mg,
0.43 mmol) and nBuLi (1.60 M in hexane, 0.25 mL, 0.40 mmol) in THF (1
mL) –15 °C, and the solution was stirred at –15 °C for 15 min to produce
25b (33 mg, 80% yield): liquid; Rf 0.77 (hexane/EtOAc 6:1); IR (neat) 1494,
[((1S*,3R*)-3-Methylcyclohexyl)methylene]dibenzene (25g): According
to the general procedure for the substitution, phosphate 24g (43 mg, 0.124
mmol) in THF (0.5 mL) was added to a solution of Ph2CH2 (67 mg, 0.40
mmol) and nBuLi (1.54 M in hexane, 0.24 mL, 0.37 mmol) in THF (0.5 mL)
at –15 °C, and the solution was stirred at –15 °C for 15 min to afford 25g
(32 mg, 98% yield): solids; mp 91–92 °C; Rf 0.47 (hexane); IR (neat) 1493,
1448, 1364, 701 cm–1 1H NMR (400 MHz, CDCl3) δ 0.80 (s, 9 H), 0.80–
;
1.05 (m, 5 H), 1.63–1.76 (m, 4 H), 2.03 (tq, J = 3.2, 10.8 Hz, 1 H), 3.43 (d,
J = 10.8 Hz, 1 H), 7.11–7.16 (m, 2 H), 7.24–7.29 (m, 8 H); 13C–APT NMR
(100 MHz, CDCl3) δ 27.3 (–), 27.6 (+), 32.4 (–), 32.6 (–), 41.5 (+), 48.1 (+),
59.7 (+), 126.0 (+), 128.2 (+), 128.4 (+), 144.7 (–); HRMS (EI+): m/z calcd
for C23H30 [M+] 306.2348, found 306.2345.
1449, 745, 702 cm–1 1H NMR (300 MHz, CDCl3) δ 0.77–0.99 (m, 4 H),
;
0.85 (d, J = 6.6 Hz, 3 H), 1.20–1.50 (m, 2 H), 1.54–1.72 (m, 3 H), 2.05 (qm,
J = ca. 11 Hz, 1 H), 3.43 (d, J = 10.8 Hz, 1 H), 7.10–7.19 (m, 2 H), 7.20–
7.35 (m, 8 H); 13C–APT NMR (75 MHz, CDCl3) δ 22.7 (+), 32.2 (–), 32.8
(+), 35.3 (–), 41.1 (+), 59.8 (+), 126.0 (+), 128.1 (+), 128.5 (+), 144.7 (–);
HRMS (FAB+): m/z calcd for C20H24 [M+] 264.1878, found 264.1878.
[((1s,4s)-4-(tert-Butyl)cyclohexyl)methylene]dibenzene
(25d):
According to the general procedure for the substitution, phosphate 24d (53
mg, 0.136 mmol) in THF (1 mL) was added to a solution of Ph2CH2 (74 mg,
0.44 mmol) and nBuLi (1.60 M in hexane, 0.26 mL, 0.42 mmol) in THF (1
mL) at –15 °C, and the solution was stirred at –15 °C for 7 h to give 25d
(32 mg, 77% yield): solids; mp 136–137 °C; Rf 0.79 (hexane/EtOAc 6:1);
IR (nujol) 1493, 1450, 1216, 758 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.91
(s, 9 H), 1.06 (tt, J = 11.8, 2.7 Hz, 1 H), 1.21–1.34 (m, 2 H), 1.37–1.50 (m,
4 H), 1.55–1.64 (m, 2 H), 2.61 (dm, J = 12.0 Hz, 1 H), 4.08 (d, J = 12.0 H,
1 H), 7.02–7.42 (m, 10 H); 13C–APT NMR (100 MHz, CDCl3) δ 21.4 (–),
27.6 (+), 28.4 (–), 32.7 (–), 36.1 (+), 48.3 (+), 51.6 (+), 126.0 (+), 128.1 (+),
128.6 (+), 144.7 (–); HRMS (EI+): m/z calcd for C23H30 [M+] 306.2348,
found 306.2345.
[((1R*,2R*)-2-Methylcyclohexyl)methylene]dibenzene
(25h):
According to the general procedure for the substitution, phosphate 24h (44
mg, 0.127 mmol) in THF (0.5 mL) was added to a solution of Ph2CH2 (68
mg, 0.40 mmol) and nBuLi (1.54 M in hexane, 0.25 mL, 0.39 mmol) in THF
(0.5 mL) at –15 °C, and the solution was stirred at –15 °C for 15 min to
produce 25h (30 mg, 90% yield): solids; mp 81–82 °C; Rf 0.84
(hexane/EtOAc 2:1); IR (nujol) 1494, 1449, 1217, 758, 703 cm–1; 1H NMR
(400 MHz, CDCl3) δ 0.82–0.93 (m, 1 H), 0.99 (d, J = 6.4 Hz, 3 H), 1.03–
1.76 (m, 8 H), 2.05 (ddt, J = 6.4, 3.4, 7.8 Hz, 1 H), 4.26 (d, J = 7.8 Hz, 1
H), 7.13–7.22 (m, 2 H), 7.23–7.32 (m, 8 H); 13C–APT NMR (100 MHz,
CDCl3) δ 20.6 (+), 23.9 (–), 24.3 (–), 26.2 (–), 32.2 (–), 32.5 (+), 45.5 (+),
52.7 (+), 125.8 (+), 126.0 (+), 128.2 (+), 128.3 (+), 128.4 (+), 129.3 (+),
143.7 (–), 145.0 (–); HRMS (FAB+): m/z calcd for C20H24 [M+] 264.1878,
found 264.1880.
[((1r,4r)-4-Methylcyclohexyl)methylene]dibenzene (25c): According to
the general procedure for the substitution, phosphate 24c (48 mg, 0.14
mmol) in THF (0.5 mL) was added to a solution of Ph2CH2 (76 mg, 0.452
mmol) in THF (0.5 mL) and nBuLi (1.54 M in hexane, 0.27 mL, 0.42 mmol)
at –15 °C, and the solution was stirred at –15 °C for 15 min to produce 25c
(25 mg, 71% yield): liquid; Rf 0.47 (hexane); IR (neat) 1598, 1492, 1450,
702 cm–1
;
1H NMR (300 MHz, CDCl3) δ 0.53 (q, J = 12.0 Hz, 1 H), 0.67–
[((3S,5S,8R,9S,10S,13S,14S,17S)-3-Benzhydryl-10,13-
0.90 (m, 2 H), 0.79 (d, J = 6.3 Hz, 3 H), 1.15–1.48 (m, 2 H), 1.50–1.73 (m,
4 H), 2.14 (tq, J = 3.3, 11.0 Hz, 1 H), 3.43 (d, J = 11.0 Hz, 1 H), 7.09–7.19
(m, 2 H), 7.20–7.40 (m, 8 H); 13C–APT NMR (75 MHz, CDCl3) δ 23.0 (+),
26.3 (–), 31.8 (–), 32.8 (+), 35.3 (–), 40.9 (–), 41.3 (+), 59.9 (+), 126.0 (+),
128.2 (+), 128.45 (+), 128.48 (+), 144.5 (–), 144.7 (–); HRMS (FAB+): m/z
calcd for C20H24 [M+] 264.1878, found 264.1879.
dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-
yl)oxy](tert-butyl)diphenylsilane (28): According to the general
procedure for the substitution, phosphate 27 (102 mg, 0.134 mmol) in THF
(0.5 mL) was added to a solution of Ph2CH2 (71 mg, 0.422 mmol) and
nBuLi (1.61 M in hexane, 0.25 mL, 0.403 mmol) in THF (0.5 mL) at –15 °C,
and the solution was stirred at –15 °C for 15 min to afford 28 (73 mg, 80%
yield): liquid; Rf 79 (hexane/EtOAc 2:1); 1H NMR (300 MHz, CDCl3) δ 0.52
(dt, J = 3.9, 12.0 Hz, 1 H), 0.74 (s, 3 H), 0.82 (s, 3 H), 1.05 (s, 9 H), 0.60–
1.75 (m, 22 H), 2.11 (ddt, J = 11.1, 2.4, 10.6 Hz, 1 H), 3.44 (d, J = 11.1 Hz,
[((1s,4s)-4-Methylcyclohexyl)methylene]dibenzene (25e): According to
the general procedure for the substitution, phosphate 24e (35 mg, 0.101
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10.1002/ejoc.201801596
European Journal of Organic Chemistry
FULL PAPER
1 H), 3.59 (t, J = 8.4 Hz, 1 H), 7.08–7.17 (m, 2 H), 7.19–7.29 (m, 8 H),
7.31–7.44 (m, 6 H), 7.67 (d, J = 7.8 Hz, 4 H); 13C–APT NMR (75 MHz,
CDCl3) δ 11.8 (+), 12.5 (+), 19.4 (–), 20.7 (–), 23.6 (–), 27.1 (+), 27.8 (–),
28.8 (–), 30.9 (–), 31.7 (–), 34.4 (–), 35.6 (+), 36.0 (–), 37.2 (–), 38.7 (–),
41.7 (+), 43.8 (–), 46.8 (+), 50.4 (+), 54.8 (+), 59.9 (+), 82.7 (+), 126.0 (+),
127.4 (+), 127.5 (+), 128.1 (+), 128.5 (+), 129.45 (+), 129.50 (+), 134.5 (+),
135.1 (+), 136.0 (+), 136.1 (+), 144.5 (–), 144.6 (–); HRMS (FAB+): m/z
calcd for C48H60OSiNa [(M+Na)+] 703.4311, found 703.4282.
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[((1R*,3R*)-3-Phenylcyclopentyl)methylene]dibenzene (32): According
to the general procedure for the substitution, phosphate 31 (42 mg, 0.106
mmol) in THF (0.5 mL) was added to a solution of Ph2CH2 (57 mg, 0.339
mmol) and nBuLi (1.61 M in hexane, 0.20 mL, 0.322 mmol) in THF (0.5
mL) at –15 °C, and the solution was stirred at –15 °C for 15 min to afford
32 (28 mg, 84% yield): liquid; Rf 0.75 (hexane/EtOAc 2:1); IR (neat) 1494,
1449, 1217, 752, 700 cm–1; 1H NMR (400 MHz, CDCl3) δ 1.24–1.40 (m, 1
H), 1.67 (dq, J = 7.8, 11.2 Hz, 3 H), 1.75–1.89 (m, 3 H), 2.06–2.15 (m, 1
H), 2.97–3.11 (m, 1 H), 3.16 (quint., J = 8.4 Hz, 1 H), 3.69 (d, J = 11.2 Hz,
1 H), 6.96–7.36 (m, 15 H); 13C–APT NMR (100 MHz, CDCl3) δ 33.1 (+),
35.1 (–), 39.5 (–), 43.5 (+), 44.7 (+), 58.9 (+), 125.8 (+), 126.1 (+), 127.1
(+), 128.1 (+), 128.3 (+), 128.5 (+), 145.1 (–), 145.2 (–), 146.5 (–); HRMS
(FAB+): m/z calcd for C24H24 [M+] 312.1878, found 312.1874.
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[((1S*,3R*)-3-Phenylcyclopentyl)methylene]dibenzene (34): According
to the general procedure for the substitution, phosphate 33 (47 mg, 0.119
mmol) in THF (0.5 mL) was added to a solution of Ph2CH2 (64 mg, 0.38
mmol) and nBuLi (1.61 M in hexane, 0.22 mL, 0.35 mmol) in THF (0.5 mL)
at –15 °C, and the solution was stirred at –15 °C for 15 min to give 34 (33
mg, 90% yield): liquid; Rf 0.75 (hexane/EtOAc 2:1); IR (neat) 1738, 1243,
756, 700 cm–1 1H NMR (300 MHz, CDCl3) δ 1.22–1.40 (m, 1 H), 1.40–
;
1.55 (m, 1 H), 1.65–1.93 (m, 2 H), 1.96–2.18 (m, 2 H), 2.83–2.98 (m, 1 H),
2.98–3.23 (m, 1 H), 3.67 (quint., J = 11.4 Hz, 1 H), 6.96–7.38 (m, 15 H);
13C–APT NMR (75 MHz, CDCl3) δ 31.3 (–), 33.2 (–), 42.1 (–), 44.5 (+),
45.8 (+), 59.1 (+), 125.9 (+), 126.1 (+), 127.0 (+), 127.9 (+), 128.0 (+),
128.2 (+), 128.3 (+), 128.5 (+), 128.6 (+), 145.0 (–), 145.2 (–), 145.9 (–);
HRMS (FAB+): m/z calcd for C24H24Na [(M+Na)+] 335.1776, found
335.1778.
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Acknowledgements
This work was supported by KAKENHI Grant Number 26410111.
Keywords: carbanions • alkylation • arenes • diarylmethyl anion
• phosphate • computational calculation
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Key Topic: Substitution
FULL PAPER
Ph
Ph
OP(O)(OPh)2
OTBS
Ph2CHLi
The substitution reactions of diphenyl
sec-alkyl phosphates with Ar2CH
anions were swift and proceeded with
inversion. In contrast, the diphenyl
substituted-cyclohexyl phosphates
proceeded with inversion, but showed
different reactivity depending on the
relative stereochemistry of the
substituent and the (PhO)2PO2
leaving group. The difference in
reactivity was rationalized by
R. Shinohara, N. Ogawa, H.
Kawashima, K. Wada, S. Saito, T.
Yamazaki, Y. Kobayashi*
OTBS
iPr
iPr
–15 °C, 15 min
94% yield, >99% es
Ph
Ph
OP(O)(OPh)2
OP(O)(OPh)2
Ph2CHLi
Page No. – Page No.
tBu
tBu
–15 °C, 15 min
tBu
80% yield
SN2 Reaction of Diarylmethyl
Anions at Secondary Alkyl and
Cycloalkyl Carbons
Ph
Ph
Ph2CHLi
–15 °C, 7 h
tBu
77% yield
computational calculation of the
transition energies.
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