Formation of COOH-Ylides, and Their Reactivities and Selectivities in Wittig Reactions

Article abstract of DOI:10.1055/s-0037-1611958

Whereas two equivalents of base are typically required to prepare carboxylate (CO ₂^-) ylides [Ph ₃ P ⁺ C ^- (H)-alk-CO ₂^- ] (alk = alkanediyl) from carboxy (CO ₂ H) pho

Full text of DOI:10.1055/s-0037-1611958

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
en
Y. Suganuma, Y. Kobayashi
Letter
Synlett
Formation of COOH-Ylides, and Their Reactivities and Selectivities
in Wittig Reactions
Yuta Suganuma
NaHDMS
Yuichi Kobayashi*
H
H
Br– Ph3P+
C
COOH
1 equiv
Department of Bioengineering, Tokyo Institute of Technology,
Box B-52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501,
Japan
ykobayas@bio.titech.ac.jp
Ph3P+ C–
COOH
H
carboxy ylides
CO2H
Alk
H
C
Alk-CHO
C
(hitherto unexplored ylides)
H
Z-olefins
Received: 18.11.2018
Accepted: 09.12.2018
Published online: 08.01.2019
DOI: 10.1055/s-0037-1611958; Art ID: st-2018-u0752-l
um salt C, which, in turn, is derived from A through initial
reaction with one equivalent of base per equivalent of A.
The pKa values7 in DMSO8 for the corresponding phosphoni-
um salts and carboxylic acids are in accordance with these
steps, and therefore, to date, C has been considered as sim-
ply an intermediate species. However, we noticed that a
mixture of A and a base in a 1:1 ratio has a reddish-orange
color, indicating the formation of the carboxy ylide D (an
acid ylide), and we therefore envisioned the use of ylide D
in a Wittig reaction. Accordingly, we present the prepara-
tion, reactivities, and Z-selectivities of the hitherto unex-
plored D-type ylides in Wittig reactions with aliphatic alde-
hydes.
Abstract Whereas two equivalents of base are typically required to
prepare carboxylate (CO2–) ylides [Ph3P+C–(H)-alk-CO2–] (alk = alkanedi-
yl) from carboxy (CO2H) phosphonium salts [(Ph3PCH2-alk-CO2H)+] X–,
we reveal, for the first time, that carboxy ylides [Ph3P+C–(H)-alk-CO2H]
can be generated with one equivalent of NaHMDS at 0 °C, and that the
Wittig reaction of simple aliphatic aldehydes (1 equiv) with these car-
boxy ylides (1.5–2 equiv) in THF at –95 to –90 °C for one hour, then at
warming temperatures to 0 °C over two hours affords (Z)-alkenoic ac-
ids. Phosphonium salts containing (CH2)n alkanediyl chains (n = 2–5)
showed adequate reactivity and high Z-selectivity, whereas shorter or
longer alkanediyl chains resulted in a low Z-selectivity and/or a low
yield. On the basis of these results with different (CH2)n chains and that
obtained with a rigid methylene group, we propose that a rapid equilib-
–
rium between Ph3PCH2-alk-CO2 and Ph3P+C–(H)-alk-CO2H, through an
intramolecular hydrogen exchange, accounts for the success of the Wit-
tig reaction.
base (2 equiv)
Br– Ph3P+
C
H
C=O
Ph3P+ C–
H
C=O
O–
O
H
H
pKa 14~23
pKa 12~13
B
A
Key words Wittig reaction, carboxy phosphonium salt, carboxy
ylides, carboxylate ylides, alkenoic acids
base
(1 equiv)
base (1 equiv)
The Wittig reaction is one of the most reliable methods
for stereoselective construction of olefinic compounds of
biological importance.1 With respect to ylides possessing
functional groups, several alkoxycarbonyl ylides (ester
ylides) have been prepared from the corresponding phos-
phonium salts and a base in a 1:1 ratio.2 However, the use of
two equivalents of base for each equivalent of carboxyphos-
phonium salt A affords the carboxylate ylide B (Scheme 1);
the latter gives a (Z)-olefin upon Wittig reaction with an al-
iphatic aldehyde in syntheses of prostaglandins (via the Co-
rey lactone),3 lipoxygenase metabolites of fatty acids,4 or
others.5 In the search for an E-selective Wittig reaction of
PhCHO with B, nonanal has been used as an additional al-
dehyde that showed a moderate Z-preference.6 It is accept-
ed that the ylide B is formed via the carboxylate phosphoni-
Br– Ph3P+
C
H
C=O
O–
Ph3P+ C–
C=O
?
O
H
H
H
C
D
Scheme 1 Carboxylate ylides B and the unexplored carboxy ylides D
(4Z)-7-Phenylhept-4-enoic acid (3) was obtained in 63%
yield upon mixing the phosphonium salt 2a and NaHMDS
in a 1:1 ratio in THF at 0 °C for one hour, followed by reac-
tion of the resulting reddish-orange mixture with 3-phen-
ylpropanal (1) at –95 to –90 °C (hereafter simplified as –
90 °C) for one hour and with subsequent warming to 0 °C
over two hours (Table 1, entry 1). For comparison, the car-
boxylate ylide, prepared from 2a and NaHMDS in a 1:2 ratio
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

B
Y. Suganuma, Y. Kobayashi
Letter
Synlett
was subjected to the Wittig reaction with 1 under similar
conditions (entry 2). The yield for entry 1 was slightly lower
than that for entry 2, but the Z/E ratios, calculated from the
heights or the integrations of the peaks in the 13C NMR
spectrum9,10 were high, with that for entry 1 being almost
same as that of entry 2. The use of fewer equivalents of
NaHMDS per equivalent of 2a was also effective (entry 3).
Table 2 Reactions under Various Conditions
initial temp. to 0 °C
THF, 3 h
+
1
2a/base (1:1)
3
(2 equiv)
(1 equiv)
Entry
Base
Initial temp (°C) Yield (%)
Z/Ea
1
2
3
4
5
6
LiHMDS
KHMDSb
t-BuOK
–90
–90
–90
0
68
44
48
65
64
61
84:16
83:17
87:13
80:20
86:14
94:6
Table 1 Preliminary Resultsa
CHO
Br– Ph3P+
CO2H
+
Ph
NaHMDS
NaHMDS
NaHMDS
1 (1 equiv)
2a (2 equiv)
–55
–105
NaHMDS (4.2, 2.0, or 1.5 equiv), THF
–90 °C, 1 h then to 0 °C, 2 h
a Ratio of peak heights in the 13C NMR.
b A toluene solution was used.
Ph
CO2H
3 (major isomer)
Entry NaHMDS (equiv) 2a/NaHMDS
Yield (%)
Z/Eb
90:10 (91:9)
NaHMDS gave 6 in reasonable yield, although the Z-selec-
tivity was low (Table 3, entry 1). Reagents derived from 2c–
e, which contain alkyl chains that are one, two, and three
carbons longer than that in 2a, gave good yields of 7,11 8,
and 9, respectively, with >92% Z-selectivity (entries 2–4).
However, 2f, which is one carbon longer than 2e, afforded
10 in only 30% yield (entry 5); moreover, the color of the
solution of 2f and NaHMDS, before the addition of 1, was far
from reddish-orange. A creamy color appeared with com-
pounds 2g–i, which possess alkyl chains that are, respec-
tively, one, two, and three carbon atoms longer than that of
2f; consequently, the Wittig products 11–13 were obtained
in quite low yields (entries 6–8). Attempts to form the ylide
from 2i by increasing the reaction time to three hours
(compared with one 1 h for the other entries) or by stirring
at room temperature were unsuccessful. In contrast, the use
1
2
3
2
1:1
63
68
60
4.2
1.5
1:2.1
1:0.75
91:9 (90:10)
90:10 (91:9)
a Initial temperature –95 to –90 °C (abbreviated as –90 °C).
b Ratios of peaks in the 13C NMR by height (by integration in parentheses).
It is evident from these results that the carboxy ylide 4
(Type D) was indeed formed from the unreactive carboxyl-
ate species 5 (Type C; Figure 1). In addition, the fact that ex-
actly one equivalent of NaHMDS is not necessarily required
is a distinct operational advantage (Table 1, entries 1 and 3).
–
Br– Ph3P+
CO2
–
Ph3P+
CO2H
4
5
Figure 1 Carboxy ylide 4 and carboxylate anion 5
Table 3 Reactions of Carboxy Ylides
NaHMDS (2 equiv)
CO2H
n
CO2H
n
+
The results that we obtained by using bases other than
NaHMDS are summarized in Table 2. LiHMDS afforded 3 in
a similar yield, but with a somewhat low Z/E ratio (Table 2,
entry 1), whereas similarly low Z/E ratios and even lower
yields were observed on using KHMDS or t-BuOK (entries 2
and 3). No reddish-orange color was observed when DBU,
NaH, or PhONa was used; aldehyde 1 was recovered in each
case (data not shown). These results are consistent with the
pKa values7,8 of the corresponding conjugate acids. Higher
temperatures of –50 °C or 0 °C resulted in lower Z/E ratios
than that obtained at –90 °C (entries 4 and 5; cf. Table 1, en-
try 1), whereas a lower temperature resulted in a higher Z/E
ratio (entry 6).
1
Br– Ph3P+
Ph
THF, –90 °C to 0 °C
6–13
2b–i (2 equiv)
n = 1, 3–9
Entry
Salt
n
Product
Yield (%)
Z/Ea
1
2b
2c
2d
2e
2f
1
3
4
5
6
7
8
9
6
7
62
70
73
74
30
~5
~5
~3
61:39
92:8
97:3
95:5
>97:3
NDc
2
3
8
4
9
5
10
11
12
13
6b
7b
8b
2g
2h
2i
ND
The method described in entry 1 of Table 1 was applied
to carboxy phosphonium salts containing alkanediyl groups
with various numbers of methylene units. The reagent de-
rived from 2b (which is one carbon shorter than 2a) and
ND
a Ratios of peak heights in the 13C NMR.
b The use of two equivalents of NaHMDS per equivalent of 2g–i gave 11–13
in yields of 70–89% and Z/E ratios of >97:3.
c ND = not determined.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

C
Y. Suganuma, Y. Kobayashi
Letter
Synlett
of two equivalents of NaHMDS per equivalent of 2g, 2h, or
2i produced olefins 11, 12, and 13 in good yields with >97%
Z-selectivity. The difference in reactivities between entries
1–4 and those of entries 6–8 are discussed latter, with addi-
tional results.
In view of the pKa values of 29–30 for simple alcohols7f
and of 14–23 for phosphonium salts,7a,b (ω-hydroxyal-
kyl)phosphonium salts should convert directly into hy-
droxy ylides on treatment with one equivalent of NaHMDS.
In fact, the addition of 1 to a mixture of phosphonium salt
17 and NaHMDS in a 1:1 ratio afforded the alkenol 18 with
93% Z-purity in 60% yield (Scheme 2, eq. 2). On the basis of
the high temperatures required for the preparation of 1,2-
oxaphospholanes and the low reactivity of these products
with aldehydes,12 the highly reactive hydroxy ylide 19 was
produced directly from 17 and remained in the solution
without changing to the less reactive 1,2-oxaphospholane
21 via alkoxide 20 (Scheme 3). To the best of our knowl-
edge, a Wittig reaction that uses hydroxy ylides has not
been reported, whereas ω-alkoxy ylides have been prepared
from various ω-hydroxy phosphonium salts and a base in a
1:2 ratio.6,13
Previously, the Wittig olefination of nonanal (14) with a
carboxylate ylide (type B ylide) derived from 2c and
LiHMDS in a 1:2 ratio at –50 °C was found to give 15 with a
Z/E ratio of 73:27 (ref. 6; Table 1, entry 53; no yield given).
We obtained 15 with a similar Z/E ratio and in 73% yield (Ta-
ble 4, entry 4). In contrast, the carboxy ylide (a type D ylide)
derived from 2c and NaHMDS in a 1:1 ratio at –90 °C afford-
ed 15 with a Z/E ratio of 97:3 and in 64% yield (entry 1). A
similar reaction at –55 °C resulted in a somewhat low Z/E
ratio (entry 2), whereas the carboxy ylide derived from
LiHMDS gave a lower Z/E ratio (entry 3). These Z-selectivity
ratios are in accord with the generally accepted fact that al-
kyl sodium ylides give higher Z/E ratios than lithium ylides.
slow
NaHMDS
0 °C, 1 h
–
Ph3P+
OH
Ph3P+
O–
17
Table 4 Comparison with the Literature Conditionsa
19
18
20
CO2H
Br– Ph3P+
Me(CH2)7CHO
1
+
–90 to 0 °C
O
2c (2 equiv)
14
Ph3P
base (2 or 4.2 equiv)
21
CO2H
Me(CH2)7CHO
THF, temp. to 0 °C, 3 h
Scheme 3 Possible changes of hydroxy ylide 19
15
Entry
Base
2c/base
Temp (°C)
Yield (%)
Z/Eb
97:3
To gain insight into the structural requirements for the
formation of the carboxy ylides, we studied reactions 1 and
2 shown in Scheme 4. In reaction 1, the cyclopropylated
phosphonium salt 22 was mixed with NaHMDS in a 1:1 ra-
tio; however, the resultant mixture was faint-yellow in col-
or, and the subsequent reaction with 1 afforded only a trace
of olefin 23.
1
2
3
4
NaHMDS
NaHMDS
LiHMDS
LiHMDS
1:1
–90
–55
–55
–55
64
65
60
73
1:1
90:10
69:31
71:29
1:1
1:2.1
a Reactions at the specified temperature for 1 h, with subsequent warming
to 0 °C over 2 h.
b Ratios of peak heights in the 13C NMR.
In contrast, the use of two equivalents of NaHMDS per
equivalent of 22 gave olefin 23 with 89% Z-selectivity in 77%
yield. In reaction 2, NaHMDS was added dropwise to a 1:1
mixture of phosphonium salt 24 and AcOH. A reddish-or-
ange color appeared shortly after each drop of the NaHMDS
solution was added, but this disappeared quickly; conse-
quently, product 25 was not obtained.
A plausible reaction pathway is summarized in Scheme
5. The equilibrium between C and D is rapidly established
within one hour at 0 °C through an intramolecular hydro-
gen exchange via E. Furthermore, the equilibrium is shifted
toward the product side owing to the insolubility of the
NaBr co-product.14 The production of D is unambiguously
indicated by the reddish-orange color. The cycloaddition of
D to aldehyde F takes place in a manner similar to that es-
tablished for alkyl ylides,15 and the resulting oxaphosphe-
tane G releases cis-olefin H as usual. In contrast, unsuccess-
ful formation of the carboxy ylides from phosphonium salts
Phosphonium salt 2j also produced diene 16 exclusively
in 70% yield (>97% Z by 13C NMR10) (Scheme 2, eq. 1). The
compatibility of the method with the somewhat acidic
methylene between two olefin groups in the product
should be useful for the synthesis of lipoxygenase metabo-
lites of unsaturated fatty acids.
Br– Ph3P+
COOH
2j (2 equiv)
(1)
COOH
1
Ph
NaHMDS (2 equiv)
THF, –90 °C to 0 °C
16, >97% Z
70%
Br– Ph3P+
OH
17 (2 equiv)
(2)
1
Ph
OH
NaHMDS (2 equiv)
THF, –90 °C to 0 °C
18, Z/E = 93:7
60%
Scheme 2 Additional experiments
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

D
Y. Suganuma, Y. Kobayashi
Letter
Synlett
Funding Information
reaction 1
Br– Ph3P+
1
+
CO2H
This work was supported by JSPS KAKENHI Grant Number
JP15H05904.
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of
S
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(J
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1
5
H
0
5
9
0
4)
(1 equiv)
22 (2 equiv)
NaHMDS (2 or 4.2 equiv)
THF, –90°C to 0 °C, 3 h
Supporting Information
Ph
CO2H
23
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611958.
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References and Notes
a Ratio of peak heights in the 13C NMR.
(1) Nicolaou, K. C.; Härter, M. W.; Gunzner, J. L.; Nadin, A. Liebigs
Ann. 1997, 1283.
reaction 2
Br– Ph3P+
(2) For example: (a) Perlmutter, P.; Selajerern, W.; Vounatsos, F.
Org. Biomol. Chem. 2004, 2, 2220. (b) Han, X.; Crane, S. N.; Corey,
E. J. Org. Lett. 2000, 2, 3437. (c) Nicolaou, K. C.; Prasad, C. V. C.;
Ogilvie, W. W. J. Am. Chem. Soc. 1990, 112, 4988. (d) Delorme,
D.; Girard, Y.; Rokach, J. J. Org. Chem. 1989, 54, 3635.
NaHMDS (1 equiv)
reddish-orange
AcOH
(1 equiv)
+
color
THF, 0 °C, 1 h
24 (1 equiv)
1
(3) For example: (a) Baars, H.; Classen, M. J.; Aggarwal, V. K. Org.
Lett. 2017, 19, 6008. (b) Prévost, S.; Thai, K.; Schützenmeister,
N.; Coulthard, G.; Erb, W.; Aggarwal, V. K. Org. Lett. 2015, 17,
504. (c) Quan, L. G.; Cha, J. K. J. Am. Chem. Soc. 2002, 124, 12424.
(d) Boulton, L. T.; Brick, D.; Fox, M. E.; Jackson, M.; Lennon, I. C.;
McCague, R.; Parkin, N.; Rhodes, D.; Ruecroft, G. Org. Process Res.
Dev. 2002, 6, 138. (e) Grieco, P. A.; Reap, J. J. J. Org. Chem. 1973,
38, 3413.
Ph
25
Scheme 4 Experiments related to the reaction mechanism
with longer methylene chains than 2f or from the cyclopro-
pane 2216 was evident from the faint-yellow to creamy col-
or observed after the addition of NaHMDS, and by the re-
covery of unreacted aldehyde 1. These results are consistent
with the inaccessibility of E owing to the long chain or to
structural restrictions.
(4) For examples, see: (a) Srinivas, J.; Namito, Y.; Matsubara, R.;
Hayashi, M. J. Org. Chem. 2017, 82, 5146. (b) Ishigami, K.;
Kobayashi, M.; Takagi, M.; Shin-ya, K.; Watanabe, H. Tetrahedron
2015, 71, 8436. (c) Critcher, D. J.; Connolly, S.; Wills, M. J. Org.
Chem. 1997, 62, 6638. (d) Wang, S. S.; Shi, X.-X.; Powell, W. S.;
Tieman, T.; Feinmark, S. J.; Rokach, J. Tetrahedron Lett. 1995, 36,
513. (e) Just, G.; Wang, Z. Y. J. Org. Chem. 1986, 51, 4796.
(5) For examples, see: (a) Ortgies, S.; Rieger, R.; Rode, K.;
Koszinowski, K.; Kind, J.; Thiele, C. M.; Rehbein, J.; Breder, A. ACS
Catal. 2017, 7, 7578. (b) Hao, H.-D.; Trauner, D. J. Am. Chem. Soc.
2017, 139, 4117. (c) Liu, Y.-T.; Chen, J.-Q.; Li, L.-P.; Shao, X.-Y.;
Xie, J.-H.; Zhou, Q.-L. Org. Lett. 2017, 19, 3231. (d) Paull, D. H.;
Fang, C.; Donald, J. R.; Pansick, A. D.; Martin, S. F. J. Am. Chem.
Soc. 2012, 134, 11128. (e) Poth, D.; Wollenberg, K. C.; Vences,
M.; Schulz, S. Angew. Chem. Int. Ed. 2012, 51, 2187; Angew.
Chem. 2012, 124, 2229. (f) Wube, A. A.; Hüfner, A.; Thomaschitz,
C.; Blunder, M.; Kollroser, M.; Bauer, R.; Bucar, F. Bioorg. Med.
Chem. 2011, 19, 567. (g) Seike, H.; Ghosh, I.; Kishi, Y. Org. Lett.
2006, 8, 3865. (h) Mascitti, V.; Corey, E. J. J. Am. Chem. Soc. 2006,
128, 3118.
–
RCHO (F)
Na+
Br– Ph3P+
C
C=O
C
D
O
H
H
+ NaBr
E
O
C
C=O
OH
H
C
H
C
H
OH
R
C
R
Ph3P
C
O
H
H
G
Scheme 5 Plausible mechanism for the formation of carboxyl ylides D
(6) Maryanoff, B. E.; Reitz, A. B.; Duhl-Emswiler, B. A. J. Am. Chem.
Soc. 1985, 107, 217.
In summary, carboxy ylides D (acid ylides) can be
formed from carboxy phosphonium salts A and one equiva-
lent of NaHMDS in THF (Scheme 1); these ylides can be
used in Wittig reactions to produce Z-alkenoic acids stereo-
selectively.17 The results obtained with various carboxy
ylides suggest that intramolecular hydrogen exchange via E
is responsible for the formation of carboxy ylides D
(Scheme 4).
(7) For pKa values in DMSO of phosphonium salts (14–23), see:
(a) Ling-Chung, S.; Sales, K. D.; Utley, J. H. P. J. Chem. Soc., Chem.
Commun. 1990, 662. (b) Zhang, X.-M.; Bordwell, F. G. J. Am.
Chem. Soc. 1994, 116, 968. For carboxylic acids (pKa= 12–13)
see: (c) Bordwell, F. G.; Algrim, D. J. Org. Chem. 1976, 41, 2507.
For HN(TMS)2 (pKa= 26), see: (d) Grimm, D. T.; Bartmess, J. E.
J. Am. Chem. Soc. 1992, 114, 1227. For HN(TMS)2 in THF
(pKa= 25.8), see: (e) Fraser, R. R.; Mansour, T. S.; Savard, S. J. Org.
Chem. 1985, 50, 3232. For t-BuOH (pKa= 32) and ROH (R = Me,
Et) (pKa= 29–30), see; (f) Olmstead, W. N.; Margolin, Z.;
Bordwell, F. G. J. Org. Chem. 1980, 45, 3295. For DBU·H+
(pKa= 14), see: (g) Hulla, M.; Chamam, S. M. A.; Laurenczy, G.;
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

E
Y. Suganuma, Y. Kobayashi
Letter
Synlett
Das, S.; Dyson, P. J. Angew. Chem. Int. Ed. 2017, 56, 10559.
Angew. Chem. 2017, 129, 10695. For PhOH (pKa= 16–18), see:
(h) Bordwell, F. G.; McCallum, R. J.; Olmstead, W. N. J. Org. Chem.
1984, 49, 1424; and also ref. 7c.
(16) A molecular model of the (E)-5-carboxypent-3-en-1-ylphos-
phonium salt, the trans-olefin analogue of 22, showed easy
access to E.
(17) (4Z)-7-Phenylhept-4-enoic acid (3; Table 1, Entry 1); Typical
Procedure
(8) (a) pKa Values in THF for most of compounds shown in ref. 7 are
not available, except for that of HN(TMS)2, which is almost the
same in THF as in DMSO.7d,e Therefore, values of other com-
pounds in DMSO are quoted for discussion of the relative acid-
ity. (b) For a collection of pKa values of compounds, see:
Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
A 1.0 M solution of NaHMDS in THF (1.0 mL, 1.0 mmol, 2 equiv)
was added to an ice-cold suspension of 2a (432 mg, 1.01 mmol,
2 equiv) in THF (5 mL). The mixture was stirred at 0 °C for 1 h
and then the resulting reddish-orange mixture was cooled to
−95 to –90 °C in a slushy mixture of hexane and liquid N2. A
solution of aldehyde 1 (67 mg, 0.50 mmol, 1 equiv) in THF (1.5
mL) was added dropwise to the mixture. After 1 h, the mixture
was warmed to 0 °C over 2 h then sat. aq NH4Cl was added. The
resulting mixture was extracted with Et2O (×3). The extracts
were combined, dried (MgSO4), and concentrated to afford a
residue that was purified by chromatography (silica gel,
hexane–EtOAc) to give a colorless liquid; yield: 66 mg (63%, Z/E
= 90:10); Rf = 0.13 (hexane–EtOAc, 4:1).
1
(9) The H NMR spectrum of 3 was superimposed with that of the
(E)-isomer, which was synthesized by a method described in
the Supplementary Information.
(10) Signal-to-noise ratios of the 1H and 13C NMR spectra were ~95%
and ~97%, respectively.
(11) Alkenoic acid 7 was previously synthesized by using 2c and t-
BuOK (1:2); the 13C NMR spectrum provided in the Supporting
Information of ref. 5a (page S97) allowed us to calculate the Z-
selectivity to be 90%, by using the peak heights.
IR (neat): 2924, 1710, 699 cm–1 1H NMR (300 MHz, CDCl3):
.
(12) Hands, A. R.; Mercer, A. J. H. J. Chem. Soc. C 1968, 2448.
(13) For examples, see: (a) Zeng, X.; Miao, C.; Wang, S.; Xia, C.; Sun,
W. Chem. Commun. 2013, 49, 2418. (b) Meyers, A. I.; Collington,
E. W. Tetrahedron 1971, 27, 5979.
(14) Phosphonium salt 2a and NaHMDS were mixed in a ratio of
0.8:1 or 2.1:1 then quenched with D2O (10 equiv). However, the
recovered material showed complicated 1H NMR spectra, which
prevented calculation of the incorporation of deuterium into 2a.
(15) (a) Byrne, P. A.; Gilheany, D. G. Chem. Soc. Rev. 2013, 42, 6670.
(b) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
(c) Maryanoff, B. E.; Reitz, A. B.; Mutter, M. S.; Inners, R. R.;
Almond, H. R. Jr.; Whittle, R. R.; Olofson, R. A. J. Am. Chem. Soc.
1986, 108, 7664.
δ = 1.5–3.0 (br s, 1 H), 2.24–2.44 (m, 6 H), 2.66 (t, J = 7.5 Hz, 2
H), 5.30–5.42 (m, 1 H), 5.42–5.53 (m, 1 H), 7.14–7.32 (m, 5 H).
13C-APT NMR (75 MHz, CDCl3): δ = 22.5 (–), 29.2 (–), 34.0 (–),
35.8 (–), 125.9 (+), 127.9 (+), 128.3 (+), 128.5 (+), 130.5 (+),
141.9 (–), 179.8 (–). HRMS (FAB+): m/z [M + Na]+ calcd for
C
13H16NaO2: 227.1048; found. 227.1045.
Note that candy-like phosphonium salts, such as 2f, or longer-
chain methylene salts were heated to form a viscous mass that
was transferred quickly to the reaction flask. After the addition
of THF and a solution of NaHMDS, the mixture was sonicated at
0 °C until the candy-like phosphonium salt that caked in the
flask was sufficiently dissolved to allow smooth stirring. The
mixture was stirred at 0 °C for a total of 1 h after the addition of
NaHMDS, then cooled to –90 °C before addition of aldehyde 1.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E