Synthesis of deuterium labeled compounds by KCN-assisted hydrolysis of phosphonium salts

Article abstract of DOI:10.1016/j.tetlet.2004.06.058

We developed a facile deuterium labeling method for benzylic or allylic halides or acetates systems. Conversion of the halides or acetates to the corresponding phosphonium salts and the following mild hydrolysis with KCN afforded the deuterium labeled compounds in good yields.

Full text of DOI:10.1016/j.tetlet.2004.06.058

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5977–5981
Synthesis of deuterium labeled compounds by KCN-assisted
hydrolysis of phosphonium salts
Ka Young Lee, Jeong Eun Na, Mi Jung Lee and Jae Nyoung Kim*
Department of Chemistry and Institute of Basic Science, Chonnam National University, Kwangju 500-757, South Korea
Received 28 April 2004; revised 24 May 2004; accepted 11 June 2004
Abstract—We developed a facile deuterium labeling method for benzylic or allylic halides or acetates systems. Conversion of the
halides or acetates to the corresponding phosphonium salts and the following mild hydrolysis with KCN afforded the deuterium
labeled compounds in good yields.
Ó 2004 Elsevier Ltd. All rights reserved.
Deuterium labeling experiments and synthesis of deu-
terium labeled compounds are very important for
detailed mechanism studies of many chemical reactions,1
studies on metabolic pathways of biologically important
molecules or drug candidates,2 and retrieving structural
details by neutron scattering,3a FTIR,3b Mass,3c and
NMR.3e;f
the hydrolysis reactions occur by the pathway shown in
Scheme 1 as exemplified with benzyltriphenylphospho-
nium bromide.5a;b;j;o;q;r Careful investigation about the
stereochemistry and on the kinetics of hydrolysis of
phosphonium salts have also been carried out.5b;j;k;q
Synthesis of D-incorporated compounds by the hydro-
lysis of phosphonium salts was also studied in part.5q
However, the classical hydrolysis of phosphonium salt
using sodium hydroxide will cause some severe problems
for the base-labile substrates. Thus, there will be needed
for the mild hydrolysis protocol in order to apply for the
base-labile substrates.
There have been reported numerous methods for the
introduction of deuterium atom into organic com-
2h
pounds.4 LiAlD4 or NaBD4-assisted reduction proto-
col4k is the most general method for the preparation of
D-incorporated simple organic compounds.
Recently, we have reported the synthesis of 5-arylpent-
4-enoates via the potassium cyanide-assisted hydrolysis
of phosphonium salts, which were derived from the
Alkaline hydrolysis of phosphonium salts have been
studied extensively,5 and there is general agreement that
OH
fast
OH
O
Ph3P
OH
Ph3P
Ph3PCH2Ph
+
CH2Ph
CH2Ph
fast
slow
fast
PhCH3
+
Ph3PO
PhCH2
H2O
Scheme 1. General base hydrolysis of phosphonium salts.
Keywords: Deuterium labeled compounds; KCN; Phosphonium salts.
* Corresponding author. Tel.: +82-62-530-3381; fax: +82-62-530-3389; e-mail: kimjn@chonnam.ac.kr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.058

5978
K. Y. Lee et al. / Tetrahedron Letters 45 (2004) 5977–5981
acetates of Baylis–Hillman adducts and phosphorous
ylide.6 During the investigation on the role of cyanide
ion for the hydrolysis of phosphonium salts, we envi-
sioned that we could prepare the useful deuterium-
labeled compounds easily.
tions and finally we found that the use of KCN in
aqueous THF is the best choice to obtain the desired
methyl 2-methylcinnamate.7h Without the aid of KCN
we could not obtain the hydrolysis product. The use of
NaN3 instead of KCN was ineffective.
We used the Baylis–Hillman acetate 1a as the first entry
in connection with our recent studies on the chemical
transformations of Baylis–Hillman adducts6;7 and on the
reduction of DABCO salts of the Baylis–Hillman ace-
tates with NaBH4.7h The reaction of 1a and triphenyl-
phosphine in H2O/THF afforded the corresponding
phosphonium salt quantitatively. The hydrolysis of the
phosphonium salt was examined under various condi-
Thus, we carried out the reaction of 1a in D2O–THF
mixed solvent in order to obtain the corresponding D-
labeled compound. As expected we obtained methyl
2-trideuteriomethylcinnamate 5a as the major product
(entry 1 in Table 1). In the 1H NMR spectrum of 5a, we
found methylene derivative 5a0 was contaminated in
about 10%.8 The mechanism for the formation of 5a and
5a0 was depicted in Scheme 3 (vide infra).
Table 1. Synthesis of deuterium-labeled compounds 5a–g
Entry
Substrate
OAc
Conditions
Products (% Yield)a
H D
1. THF/D2O, Ph3P (1.2 equiv)
rt, 3 h
COOMe
CD3
COOMe
D
COOMe
Br
1
2. KCN (1.2 equiv)
rt, 1 h
D
5a'
1a
5a
(81%, 9:1)
CD3
1. THF/H2O, Ph3P (1.2 equiv)
rt, 12 h, 100%
2
2. THF/D2O, KCN (1.1 equiv)
40–50 °C, 13 h
1b
5b (82)
1. THF/D2O, Ph3P (2.4 equiv)
50–60 °C, 48 h
2. KCN (2.4 equiv)
Cl
D3C
CD3
3
4
Cl
5c (82)
40–50 °C, 14 h
1c
O
O
1. THF/D2O, Ph3P (1.2 equiv)
rt, 20 h
Br
CD3
2. KCN (1.2 equiv)
50 °C, 12 h
1d
5d (61)
O
O
1. THF/D2O, Ph3P (1.2 equiv)
50 °C, 36 h
2. KCN (1.2 equiv)
Cl
CD3
5
6
50–60 °C, 48 h
1e
5e (72)
CD3
1. THF/D2O, Ph3P (1.2 equiv)
rt, 12 h
Br
MeOOC
MeOOC
5f (89)
2. KCN (1.2 equiv)
rt, 24 h
1f
1. THF/D2O, Ph3P (1.2 equiv)
rt, 3 h
Br
O2N
O2N
CD3
7
8
O
O
2. KCN (1.2 equiv)
rt, 3 h
1g
5g (88)
CD3
Br
1. THF/D2O, Ph3P (1.2 equiv)
50–60 °C, 20 h
2. KCN (1.2 equiv)
5h (0)b
1h
50–60 °C, 48 h
a Mixtures of the corresponding compounds –CHD2, –CH2D, and/or –CH3 were contaminated in trace amounts (2–5%) based on 1H NMR spectra
of 5a–g.
b 4 h was isolated in 80%.10

K. Y. Lee et al. / Tetrahedron Letters 45 (2004) 5977–5981
5979
KCN
D2O/THF
heating
Ph3P
D2O (or H2O)/THF
rt
D
D
H
H
H
H
D
PPh3
Br
Ph3P=O
Br
2b
5b
1b
K
CN
H
H
PPh3
PPh3
D
D
PPh3
I
Br
O
D2O
D
D
III
H
D
PPh3
Br
hydrolysis
3b
K
CN
D
D
D
D
D2O
PPh3
PPh3
PPh3
Br
4b
II
Scheme 2. Proposed reaction mechanism for the conversion of 1b into 5b.
H
H
COOMe
PPh3
COOMe
1a
D
D
H
PPh3
H
H
D
H
D
COOMe
D
COOMe
D
5a'
5a
Scheme 3.
In order to understand the reaction mechanism we
examined the reaction with more structurally simple
substrate 1b. The reaction of 1b and Ph3P in D2O/THF
gave the corresponding phosphonium salt 2b quantita-
reaction mechanism as in Scheme 2. During the prepa-
ration of phosphonium salt the benzylic proton cannot
be exchanged with deuterium in solvent. The basicity of
bromide ion is so weak that it cannot deprotonate the
benzylic proton of 2b. However, when the KCN was
introduced, the cyanide ion can deprotonate the weakly
acidic benzylic proton to generate the corresponding
ylide I in part. Thus, the deuterium–proton exchange
can occur to afford 3b as an intermediate. Same process
occurred once again to produce 4b, and eventually 5b
1
tively.9 However, the H NMR spectrum of the phos-
phonium salt at this stage did not show any deuterium
incorporation.9 But, when we performed the following
KCN-assisted hydrolysis step in D2O/THF, we could
obtain the deuterium-labeled compound 5b in 82% yield.
From these results we tentatively propose the whole

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K. Y. Lee et al. / Tetrahedron Letters 45 (2004) 5977–5981
3. For the importance of D-labeled compounds in structural
determinations, see: (a) Zeng, X. B.; Ungar, G. Macro-
molecules 2003, 36, 4686; (b) Bateman, J. E.; Eagling, R.
D.; Horrocks, B. R.; Houlton, A. J. Phys. Chem. B 2000,
104, 5557; (c) Amelung, W.; Brodowski, S. Anal. Chem.
2002, 74, 3239; (d) Yu, X.; Pawliszyn, J. Anal. Chem. 2000,
72, 1788; (e) Brotin, T.; Lesage, A.; Emsley, L.; Collet, A.
J. Am. Chem. Soc. 2000, 122, 1171; (f) Adams, C. H.;
Brereton, M. G.; Hutchings, L. R.; Klein, P. G.; McLeish,
T. C. B.; Richards, R. W.; Ries, M. E. Macromolecules
2000, 33, 7101.
4. For the introduction of deuterium atom into organic
compounds, see: (a) Sajiki, H.; Aoki, F.; Esaki, H.;
Maegawa, T.; Hirota, K. Org. Lett. 2004, 6, 1485; (b)
Concellon, J. M.; Rodriguez-Solla, H.; Concellon, C.
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Weigelt, S.; Sewald, N. Synlett 2004, 726; (e) Concellon, J.
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Eames, J.; Coumbarides, G. S.; Suggate, M. J.; Wee-
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J. M.; Bardales, E.; Llavona, R. J. Org. Chem. 2003, 68,
1585; (h) Labuschagne, A. J. H.; Schneider, D. F.
Tetrahedron Lett. 1983, 24, 743; (i) Shattuck, J. C.;
Meinwald, J. Tetrahedron Lett. 1997, 38, 8461; (j) Lygo,
B.; Humphreys, L. D. Tetrahedron Lett. 2002, 43, 6677; (k)
Audia, J. E.; Colocci, N. Tetrahedron Lett. 1991, 32, 3779;
(l) Duralski, A. A.; Watts, A. Tetrahedron Lett. 1992, 33,
4983; (m) Theobald, P. G.; Okamura, W. H. Tetrahedron
Lett. 1987, 28, 6565; (n) Chin, T.-S.; Wolinska-Mocydlarz,
J.; Leitch, L. C. J. Labelled Compds. 1970, 6, 285; (o)
Lauer, W. M.; Koons, C. B. J. Org. Chem. 1959, 24, 1169;
(p) Yao, J.; Evilia, R. F. J. Am. Chem. Soc. 1994, 116,
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according to the well-known hydrolysis mecha-
nism.5a;b;j;o;q;r During the last hydrolysis step the cyanide
also acts in anyway. But, we cannot say exactly the role
of the cyanide ion at this stage.
The representative results are summarized in Table 1. As
shown, the reaction can be applicable to both of bro-
mides, chlorides, and acetates. The reaction can be used
for the benzylic type and phenacyl type substrates. The
reaction can also be applicable to the base-labile sub-
strates like as 1a or 1f. However, unfortunately, the
hydrolysis of simple alkyl bromides like as 1-bromo-3-
phenylpropane (1h) failed (entry 8 in Table 1). In this
case, as mentioned in earlier papers5 the corresponding
phosphonium salt cannot be hydrolyzed into the desired
compound due to the bad leaving group ability of the 3-
phenylpropyl anion moiety. Instead, we isolated the
corresponding D-labeled phosphonium salt 4h in 80%
yield.10
In summary, we developed a facile deuterium labeling
method for benzylic halides, allylic acetates, and
phenacyl halides. Conversion of the halides or acetates
to the corresponding phosphonium salts and the fol-
lowing mild hydrolysis with KCN afforded the deute-
rium labeled compounds in good yields.
Acknowledgements
This work was supported by Korea Research Founda-
tion Grant (KRF-2002-015-CP0215).
5. For the hydrolysis of phosphonium salts, see: (a) Johnson,
A. W.; Kaska, W. C.; Starzewski, K. A. O.; Dixon, D. A.
Ylides and Imines of Phosphorus; John Wiley & Sons: New
York, 1993; (b) Zanger, M.; VanderWerf, C. A.; McEwen,
W. E. J. Am. Chem. Soc. 1959, 81, 3806; (c) Fenton, G.
W.; Ingold, C. K. J. Chem. Soc. 1929, 2342; (d) Horner,
L.; Hoffmann, H.; Wippel, H. G.; Hassel, G. Chem. Ber.
1958, 91, 52; (e) Hoffmann, H. Annalen 1960, 634, 1; (f)
Aksnes, G.; Songstad, J. Acta Chem. Scand. 1962, 16,
1426; (g) Hudson, R. F.; Green, M. Angew. Chem., Int.
Ed. Engl. 1963, 2, 11; (h) McEwen, W. E. Topics
Phosphorus Chem. 1965, 2, 1; (i) Luckenbach, R. Phos-
phorus 1972, 1, 223; (j) McEwen, W. E.; Kumli, K. F.;
Blade-Font, A.; Zanger, M.; VanderWerf, C. A. J. Am.
Chem. Soc. 1964, 86, 2378; (k) McClelland, R. A.; McGall,
G. H.; Patel, G. J. Am. Chem. Soc. 1985, 107, 5204; (l)
Gilheany, D. G.; Kelly, P. G.; Mitchell, C. A.; Walker, B.
J.; Malone, J. F.; Blaney, J.; Wilson, R. Phosphorus Sulfur
Silicon 1993, 75, 11; (m) Cristau, H.-J.; Mouchet, P.
Phosphorus Sulfur Silicon 1995, 107, 135; (n) Gilheany, D.
G.; Thompson, N. T.; Walker, B. J. Tetrahedron Lett.
1987, 28, 3843; (o) Corfield, J. R.; Trippett, S. Chem.
Commun. 1970, 1267; (p) Allen, D. A.; Grayson, S. J.;
Harness, I.; Hutley, B. G.; Mowat, I. W. J. Chem. Soc.,
Perkin Trans. 2 1973, 1912; (q) Schlosser, M. Chem. Ber.
1964, 97, 3219; (r) Schnell, A.; Tebby, J. C. J. Chem. Soc.,
Perkin Trans. 1 1977, 9, 1883.
References and notes
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Soc. 2002, 124, 14403; (b) Abe, M.; Adam, W.; Ino, Y.;
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M.; Stratakis, M. J. Org. Chem. 2002, 67, 8395; (g)
Johnstone, R. A. W.; Price, P. J. Tetrahedron 1985, 41,
2493.
2. For the study of biological pathways, see: (a) Goese, M.;
Eisenreich, W.; Kupfer, E.; Stohler, P.; Weber, W.;
Leuenberger, H. G.; Bacher, A. J. Org. Chem. 2001, 66,
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Zhang, Y. H.; Yan, X.; Maier, C. S.; Schimerlik, M. I.;
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C.; Woo, N.-T.; Yorgey, P.; Gould, S. J. Tetrahedron Lett.
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2002, 30, 107.
6. Im, Y. J.; Na, J. E.; Kim, J. N. Bull. Korean Chem. Soc.
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7. For our recent publications on the Baylis–Hillman reac-
tion, see: (a) Kim, J. M.; Lee, K. Y.; Lee, S.-k.; Kim, J. N.
Tetrahedron Lett. 2004, 45, 2805; (b) Lee, K. Y.; Kim, J.
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2003, 44, 2987; (e) Lee, K. Y.; Kim, J. M.; Kim, J. N.
Synlett 2003, 9, 357; (f) Kim, J. N.; Lee, H. J.; Lee, K. Y.;
Gong, J. H. Synlett 2002, 173; (g) Chung, Y. M.; Gong, J.
H.; Kim, T. H.; Kim, J. N. Tetrahedron Lett. 2001, 42,
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1265 cmꢀ1; H NMR (CDCl3) d 7.21 (d, J ¼ 8:4 Hz, 4H),
7.46 (d, J ¼ 8:4 Hz, 4H); 13C NMR (CDCl3) d 20.21
(septet, J ¼ 19:0 Hz), 126.77, 129.41, 136.53, 138.28; Mass
(70 eV) m=z (rel. intensity) 77 (39), 92 (69), 170 (75), 187
(75), 188 (Mþ, 100); 5d: IR (neat) 2252, 1678, 1284 cmꢀ1
;
1H NMR (CDCl3) d 7.52–7.63 (m, 2H), 7.86–8.05 (m, 4H),
8.46 (d, J ¼ 0:6 Hz, 1H); 13C NMR (CDCl3) d 26.19
(septet, J ¼ 19:5 Hz), 123.86, 126.76, 127.77, 128.41,
128.46, 129.53, 130.18, 132.49, 134.47, 135.58, 198.23;
Mass (70 eV) m=z (rel. intensity) 63 (37), 77 (31), 127 (100),
155 (65), 173 (Mþ, 23). 5e4o: IR (neat) 2256, 1682,
8. Typical procedure for the synthesis of 5b: A solution of
2-bromonaphthalene (1b, 207 mg, 1 mmol) and Ph3P
(315 mg, 1.2 mmol) in D2O/THF (2 mL, 1:1) was stirred
at room temperature for 12 h. To the reaction mixture
KCN (72 mg, 1.1 mmol) was added and stirred at 50 °C for
13 h. After usual workup procedure and column chro-
matographic purification process (hexane/ether, 20:1), 5b
was separated as clear oil, 120 mg (82%). Other D-labeled
compounds were prepared similarly and the spectroscopic
data are as follows. 5a: IR (neat) 2214, 2121, 2063, 1712,
1
1261 cmꢀ1; H NMR (CDCl3) d 7.43–7.50 (m, 2H), 7.54–
7.60 (m, 1H), 7.94–7.99 (m, 2H); 13C NMR (CDCl3) d
26.17 (septet, J ¼ 19:1 Hz), 128.31, 128.58, 133.13, 137.11,
198.33; Mass (70 eV) m=z (rel. intensity) 51 (100), 77 (81),
105 (76), 123 (Mþ, 29). 5f: IR (neat) 2360, 2210, 2129,
2056, 1724, 1281 cmꢀ1; H NMR (CDCl3) d 3.89 (s, 3H),
1
7.22 (d, J ¼ 8:4 Hz, 2H), 7.92 (d, J ¼ 8:4 Hz, 2H); 13C
NMR (CDCl3) d 20.74 (septet, J ¼ 19:2 Hz), 51.86,
127.37, 129.00, 129.52, 143.37, 167.12; Mass (70 eV) m=z
(rel. intensity) 47 (100), 49 (92), 67 (29), 84 (83), 122 (55),
1
1257 cmꢀ1; H NMR (CDCl3) d (major, 5a) 3.81 (s, 3H),
7.26–7.39 (m, 5H), 7.70 (s, 1H); (minor, 5a0) 3.60 (t,
J ¼ 2:1 Hz, 1H), 3.72 (s, 3H), 7.26–7.39 (m, 5H); 13C
NMR (CDCl3) d (major, 5a) 13.25 (septet, J ¼ 19:5 Hz),
51.97, 128.24, 128.30, 128.35, 129.55, 135.80, 138.96,
169.07; (minor, 5a0) 37.56 (t, J ¼ 19:5 Hz), 51.78, 167.30,
and other remaining six peaks cannot readable correctly;
Mass (70 eV) m=z (rel. intensity) 40 (96), 59 (92), 117 (63),
118 (62), 119 (60), 120 (62), 148 (43), 179 (Mþ, 100). 5b4n:
153 (Mþ, 21). 5g: IR (neat) 2357, 2218, 1493, 1358 cmꢀ1
;
1H NMR (CDCl3) d 6.29 (d, J ¼ 3:6 Hz, 1H), 7.25 (d,
J ¼ 3:6 Hz, 1H); 13C NMR (CDCl3) d 13.49 (m), 110.04,
113.18, 151.34, 156.80; Mass (70 eV) m=z (rel. intensity) 45
(100), 63 (13), 100 (7), 130 (Mþ, 100).
9. In some cases, we separated the phosphonium salt and
examined the 1H NMR spectrum in order to check the
D-incorporation. 2b: 1H NMR (DMSO-d6) d 5.36 (d,
J ¼ 15:9 Hz, 2H), 7.06 (d, J ¼ 8:4 Hz, 1H), 7.47–7.95 (m,
21H). 2c: 1H NMR (DMSO-d6) d 5.29 (d, J ¼ 15:6 Hz,
4H), 7.04 (d, J ¼ 8:1 Hz, 4H), 7.52 (d, J ¼ 8:1 Hz, 4H),
7.50–7.92 (m, 30H).
1
IR (neat) 2225, 2202, 2125, 2060 cmꢀ1; H NMR (CDCl3)
d 7.26–7.30 (m, 1H), 7.34–7.44 (m, 2H), 7.58 (s, 1H), 7.69–
7.78 (m, 3H); 13C NMR (CDCl3) d 20.84 (septet,
J ¼ 19:1 Hz), 124.91, 125.82, 126.82, 127.21, 127.57,
127.65, 128.07, 131.69, 133.65, 135.28; Mass (70 eV) m=z
(rel. intensity) 43 (100), 58 (40), 144 (17), 145 (Mþ, 28).
5c2h: mp 118–119 °C; IR (neat) 2222, 2129, 2052,
10. 1H NMR (DMSO-d6) d 1.82 (m, 2H), 2.82 (m, 2H), 7.15–
7.21 (m, 3H), 7.25–7.31 (m, 2H), 7.74–7.95 (m, 15H).