Synthesis of different deuterated carboxylic acids from unsaturated acids promoted by samarium diiodide and D2O

Article abstract of DOI:10.1002/1521-3765(20021004)8:19<4493::AID-CHEM4493>3.0.CO;2-U

An easy, and rapid reduction of the C=C bond of α,β-unsaturated acids by means of samarium diiodide in the presence of D₂O provides an efficient method for synthesizing 2,3-dideuterio acids. Starting from alka-2,4-dienoic acids, (E)-α,δ-dideuterio-βγ-unsaturated acids are obtained, the new C=C bond being generated with complete diastereoselectivity. When H₂O is used instead of D₂O, saturated carboxylic acids and (E)-β,γ-unsaturated acids are isolated. A mechanism to explain each synthesis has been proposed.

Full text of DOI:10.1002/1521-3765(20021004)8:19<4493::AID-CHEM4493>3.0.CO;2-U

FULL PAPER
Synthesis of Different Deuterated Carboxylic Acids from Unsaturated Acids
Promoted by Samarium Diiodide and D2O
Jose¬ M. Concello¬n* and Humberto RodrÌguez-Solla[a]
ˆ
Abstract: An easy, and rapid reduction of the C C bond of a,b-unsaturated acids by
means of samarium diiodide in the presence of D2O provides an efficient method for
synthesizing 2,3-dideuterio acids. Starting from alka-2,4-dienoic acids, (E)-a,d-
Keywords: acids
reduction ¥ samarium
¥
deuterium
¥
ˆ
dideuterio-bg-unsaturated acids are obtained, the new C C bond being generated
with complete diastereoselectivity. When H2O is used instead of D2O, saturated
carboxylic acids and (E)-b,g-unsaturated acids are isolated. A mechanism to explain
each synthesis has been proposed.
In relation to the synthetic application of samarium
diiodide in organic synthesis, only one paper describing a
general conjugated reduction of a,b-unsaturated acids pro-
moted by SmI2 has been reported; hexamethylphosphoric
triamide (HMPA) was required as an additive to facilitate the
reduction.[8] In addition to this paper, only one case exists of
the reduction of an a,b-unsaturated acid (cinnamic acid); this
was achieved by using a solution of SmI2/methanol/THF[9] or
by using samarium metal and iodine in methanol.[10]
Despite that the presence of H2O increases the reducing
power of SmI2,[11] to the best of our knowledge, the simpler
1,2-reduction of conjugated carboxylic acid derivatives using
SmI2 and D2O or H2O (without additives) has not been
described.
Previously we described two practical methodologies for
the synthesis of various deuterated compounds such as 2,3-
dideuterioesters or amides[12] and (E)-a,d-dideuterio-b,g-un-
saturated esters.[13]
In the present contribution we describe a novel and rapid
method to obtain 2,3-dideuterio acids or saturated acids 2 by
Introduction
Relatively few general methods for the selective conjugated
reduction of a,b-unsaturated carboxylic acids and their
derivatives are known.[1] However, this reactivity pattern is
useful for the direct reduction of unsaturated carboxylic acids
because it circumvents synthetic designs requiring conjugate
reduction through an ester, where efficient protection de-
protection schemes are necessitated.
Isotopically labeled compounds are very useful to establish
the mechanism of organic reactions and the biosynthesis of
many natural compounds.[2]
The selective conjugated reduction of a,b-unsaturated
carboxylic acids and their derivatives is a useful reaction in
organic chemistry and has been achieved using a number of
methodologies.[1] However, the conjugated reduction of a,b-
unsaturated acids using deuterium instead of hydrogen has
been scarcely reported. Traditionally, such transformations were
performed with special deuteration catalysts, although successful
examples of selective deuteration of other types are still rare.
To the best of our knowledge, only three alternative
ˆ
an efficient reduction of the C C double bond of conjugated
[3]
methodologies to the catalytic addition of D2 to a,b-
carboxylic acids. The reaction was promoted by SmI2 in the
presence of D2O or H2O, respectively.
unsaturated acids have been described:[4] by using enzymes
in D2O,[5] by diimide reductions using potassium azodicarbox-
ylate,[6] and by using deuterated formic acid/triethylamine as
the deuterium source.[7] For this reason, the development of
an effective general method for the synthesis of 2,3-dideuterio
acids is of significant value.
When alka-2,4-dienoic acids were used as starting com-
pounds, the SmI2 promoted 1,4-reduction of the two conju-
ˆ
gated C C bonds provides a,d-dideuterio-b,g-unsaturated
ˆ
acids 8, in which the new C C bond is generated with
complete diastereoselectivity. Other labeled compounds have
been also obtained.
¬
[a] Dr. J. M. Concellon, H. RodrÌguez-Solla
¬
¬
Departamento de QuÌmica Organica e Inorganica
Facultad de QuÌmica, Universidad de Oviedo
33071 Oviedo (Spain)
Fax : (‡34) 98 510 34 46
Results and Discussion
Synthesis of aromatic 2,3-dideuterio acids: Our first attempts
involved the preparation of aromatic 2,3-dideuterio acids.
E-mail: jmcg@sauron.quimica.uniovi.es
Chem. Eur. J. 2002, 8, No. 19
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0819-4493 $ 20.00+.50/0
4493

J. M. ConcellÛn and H. RodrÌguez-Solla
FULL PAPER
Thus, the aromatic a,b-unsaturated carboxylic acids (1 equiv)
were previously stirred with a solution of D2O (2 mL) in THF
(2 mL) for 5 min at room temperature. After this treatment, a
solution of SmI2 (3 equiv) in THF (15 mL) was added, and the
resulting solution was stirred for 10 min at room temperature,
affording after acidification with HCl the corresponding
aromatic 2,3-dideuterio acids 2 in high yield. (Scheme 1,
X ˆ D, and Table 1).
It is noteworthy that D2O is the cheapest deuteration
reagent for obtaining isotopically labeled organic compounds,
and cinnamic derivatives have been widely used in biological
activities.[15]
Synthesis of labeled compounds 2 may be explained by
assuming that the SmI2-promoted 1,4-reduction of 1 is
initiated by oxidative addition of SmI2 to generate the enolate
[16]
4; this radical is then hydrolyzed by the protic medium
(X ˆ D), and afford the corresponding radical 5. After a
second electron transfer from SmI2 the radical generated the
anion 6, this being hydrolyzed by D2O to afford the
corresponding compound 2 (Scheme 2). When the a,b-
unsaturated acids were not pre-treated with D2O, a compet-
itive hydrolysis of 4 and 6 produced by the acid proton of the
carboxylic group and D2O afforded a mixture of mono-, di-,
and non-deuterated compounds. The pretreatment of 1 with
D2O could also change the aggregation state of the substrate,
avoiding intermolecular hydrogen transfers.
Table 1. Synthesis of aromatic 2,3-dideuterio acids.
Entry
1
2
R1
R2
X
D
Yield [%][a]
77
2a
H
2
3
4
2b
2c
2d
H
H
H
D
D
D
71
73
85
Synthesis of aliphatic 2,3-dideuterio acids: When the treat-
ment with SmI2 and D2O was performed with aliphatic a-
substituted-a,b-unsaturated acids or diacids, the correspond-
ing 2,3-dideuterio acids 2g i were isolated in high yields
(Table 2). Starting from unsaturated diacids, no differences
were observed when Z or E diacids were used, and 2,3-
dideuteriobutanedioic acid was obtained, for example, from
maleic and fumaric acids (Table 2, entries 1 and 2).
5
6
2e
2 f
Me
H
D
H
82
74
[a] Isolated yield based on compound 1.
O
X
O
1) X2O
R1
OH
R1
OH
2) SmI2
3) H3O+
R2
R2
X
Table 2. Synthesis of aliphatic 2,3-dideuterio acids.
1
2
Entry
2
R1
R2
Yield [%][a]
Scheme 1. Synthesis of 2,3-dideuterio acids 2.
1
2
3
4
2g
2g
2 h
2i
HO2C[b]
HO2C[c]
C7H15
H
H
Me
Me
61
65
71
77
The reaction sequence is rather crucial in this case: When
the aromatic a,b-unsaturated acids were not pre-treated with
D2O and the reaction of 1 was carried out directly with SmI2
and D2O, a mixture of mono-, di-, and non-deuterated
aromatic acid was obtained.
C6H11
[a] Isolated yield based on compound 1. [b] From maleic acid. [c] From
fumaric acid.
Aromatic a,b-unsaturated acids in which the double bond is
di- or trisubstituted can be reduced and the reaction is also
tolerant to aromatic rings with different functional groups, see
Table 1.
The position of deuteration was established by 1H and
13C NMR spectrometry of compounds 2, while the complete
deuterium incorporation was determined by mass spectro-
scopy, and was found to be >99%.[14] These 2,3-dideuterio
acids were isolated as mixture of diastereoisomers (ranging
between 2:1 to 1:1).
However, when aliphatic, non-a-alkylated acids (Scheme 1,
R2 ˆ H) were used as starting compounds, no reduction took
place and the a,b-unsaturated acids were recovered.[17] This
different behaviour with respect to the aromatic or conjugated
acids may be explained taking into account that the initial
oxidative addition of SmI2 is favoured in the case of aromatic
acids with respect to the aliphatic non-a-substituted acids,
due to the enolate radical 4 (Scheme 2) being stabilized by
O
OSmI2
OX
OSmI2
SmI2
X2O
¬
Abstract in Spanish: Se describe una nueva metodologÌa facil,
R1
OX
R1
R1
O
1
X
R2
R2
R2
¬
sencilla y general para reducir acidos carboxÌlicos a,b-insatu-
¬
rados, promovida por SmI2 y D2O, obteniendose 2,3-dideuterio
3
4
5
¬
¬
acidos. Si se utilizan como productos de partida acidos
SmI2
¬
carboxÌlicos alca-2,4-dienoicos, se obtienen acidos carboxÌlicos
(E)-a,d-dideuterio-b,g-insaturados en los que el nuevo enlace
SmI2 OSmI2
O
ˆ
X
O
¬
C C se genera con total diastereoseleccion. Cuando se emplea
1) X2O
2) H3O+
R1
R1
OH
¬
H2O en lugar de D2O, se aislan acidos carboxÌlicos saturados o
R2
X
R2
X
¬
acidos (E)-b,g-insaturados. Se propone un mecanismo para
explicar cada proceso.
2
6
Scheme 2. Mechanism of the reduction reaction.
4494
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 0947-6539/02/0819-4494 $ 20.00+.50/0 Chem. Eur. J. 2002, 8, No. 19

Deuterated Carboxylic Salts
4493 4497
resonance. In addition, the enolate radical derived from
diacids or aliphatic a-substituted-a,b-unsaturated acids is
more stable than that derived from non-a-alkylated a,b-
unsaturated acids due to resonance, in the first case, and to
7
X2O
O
OSmI2
OX
OSmI2
SmI2
R1
OX
R1
R1
O
X
ˆ
higher substitution of the C C bond in the second.
9
10
11
Preparation of (E)-a,d-dideuterio-b,g-unsaturated acids: Iso-
topically labeled (E)-b,g-unsaturated acids 8 can be prepared
by using the described reaction conditions (Scheme 3) and
starting, in this case, from alka-2,4-dienoic acids 7 (Table 3).
SmI2
OSmI2
O
SmI2 OSmI2
SmI2
R1
R1
O
X
X
O
X
O
12
1) X2O
R1
OH
R1
OH
2) SmI2
3) H3O+
1) X2O
2) H3O+
X
7
8
Scheme 3. Synthesis of (E)-a,d-dideuterio-b,g-unsaturated acids 8.
X
O
R1
OH
X
Table 3. Synthesis of (E)-b,g-unsaturated acids.
8
R1
X
ds[a]
Yield [%][b]
Scheme 4. Proposed mechanism for the conversion of 7 into 8.
Entry
8
1
2
3
8a
8b
8c
H
Me
Me
D
D
H
> 98
> 98
> 98
61
77
75
plained by taking into account that the carboxylate C-5 anion
structure is more stable than the carboxylate C-3 anion
structure; this as a result of the charge repulsions and the
steric hindrance produced by the two samarium atoms.
ˆ
[a] Diastereoisomeric purity (ds) of the new C C bond generated was
determined by GC-MS and 300 MHz 1H and 13C NMR analysis of the crude
products 8. [b] Isolated yield based on compound 7.
Synthesis of saturated or b,g-unsaturated acids: No differ-
ences were observed in the reaction when D2O or H2O was
used as proton source, and consequently saturated acids
(Table 1, entry 6) and b,g-unsaturated carboxylic acids (Ta-
ble 3, entry 3) can be obtained by reaction of SmI2 in the
presence of H2O with 1 or 7, respectively. In these cases no
pre-treating of the a,b-unsaturated acids with H2O was
necessary.
These labeled unsaturated compounds were synthesized
through an SmI2 promoted 1,4-reduction of the two conju-
ˆ
ˆ
gated C C bonds (see mechanism), generating the new C C
bond with total diastereoselectivity. The incorporation of
deuterium generated a new stereogenic centre and conse-
quently the deuterated compounds 8 were isolated as a
roughly 1:1 mixture of diastereoisomers.[18]
The diastereoisomeric purity of 8 was determined on the
crude reaction products by 1H NMR spectroscopy (300 MHz).
The positions of the newly generated double bond and the
deuterium atoms were established by 1H and 13C NMR
spectroscopy of compounds 8. Analysis of the multiplicity of
the signals of the alkene protons allowed us to establish the
proposed structure (Scheme 3) and to verify that the product
was not a result of a possible 1,2-reduction of the two con-
Synthesis of other deuterated carboxylic acids: The described
methodology can be applied to obtain 3-deuterated carboxylic
acids as depicted below. Thus, the treatment of the 2,3-
dideuterio acid 2e with LDA and further hydrolysis with H2O
afforded the corresponding 3-deuterio acid 13e in 75% yield.
D
D
ˆ
jugated C C bonds (a,b-dideuterated-g,d-unsaturated acids).
CO2H
Me
CO2H
Me
ˆ
The E-stereochemistry in the C C bond was established on
D
the basis of the value of the 1H NMR coupling constant
between the olefinic protons of compounds 8. Complete
deuterium incorporation (>99%) was confirmed by mass
spectrometry.[14]
2e
13e
D
O
D
O
Me
OH
Me
OH
Synthesis of 8 may be explained by assuming that the SmI2-
promoted 1,4-reduction of the two conjugated double bonds
D
D
8b
14b
ˆ
C C, is initiated by oxidative addition of SmI2 generating
enolate radical 10,[16] which is hydrolyzed by the acid medium
(X ˆ D). The resulting radical 11 suffers a second electron
transfer from SmI2 affording an allylic anion 12, and the
hydrolysis of 12 with D2O produces the corresponding
compound 8 (Scheme 4).
ˆ
Taking into account that the C C bond of a,d-dideuterio-
b,g-unsaturated acids can be easily hydrogenated, the pro-
posed methodology can be used to prepare saturated a,d-
dideuterio acids. In this respect, 2,5-dideuteriohexanoic acid
14b was prepared by hydrogenation of 8b by using Rh/Al2O3
as catalyst[19] in 82% yield (Figure 1).
The C5 deuteration instead of C3 deuteration of the allyl
anion 12 (1,4-reduction versus 1,2-reduction) may be ex-
Chem. Eur. J. 2002, 8, No. 19
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0819-4495 $ 20.00+.50/0
4495

J. M. ConcellÛn and H. RodrÌguez-Solla
FULL PAPER
6.58 (dd, J ˆ 8.26, 1.99 Hz, 1H), 2.66 (d, J ˆ 7.40 Hz, 1H), 2.50 (d, J ˆ
7.40 Hz, 1H); 13C NMR (75 MHz, D2O): d ˆ 177.9 (C), 143.7 (C), 142.1
(C), 133.3 (C), 120.4 (CH), 116.1 (CH), 116.0 (CH), 35.1 (t, J ˆ 19.5 Hz,
It is noteworthy that synthesis of deuterated carboxylic
acids in a carbon atom different to the a-position is very
difficult to achieve.
‡
CHD), 29.1 (t, J ˆ 19.8 Hz, CHD); MS (70 eV): m/z (%): 184 (26) [M] , 124
(100), 108 (18), 78 (13); HRMS: calcd for C9H8D2O4: 184.0703; found:
184.0705; IR (neat): nÄ ˆ 3399, 3052, 2994, 1660 cmÀ1; Rf ˆ 0.2 (hexane/
AcOEt 1:1).
Conclusion
2,3-Dideuterio-3-(4-hydroxy-3-methoxyphenyl)propionic
acid
(2d):
1H NMR (200 MHz, CDCl3): d ˆ 6.85 (d, J ˆ 8.46 Hz, 1H), 6.74 6.68 (m,
2H), 3.85 (s, 3H), 2.88 (d, J ˆ 7.70 Hz, 1H), 2.64 (d, J ˆ 7.70 Hz, 1H);
13C NMR (50 MHz, CDCl3): d ˆ 179.0 (C), 146.3 (C), 143.8 (C), 131.9 (C),
120.6 (CH), 114.3 (CH), 110.8 (CH), 55.7 (CH3), 35.5 (t, J ˆ 19.9 Hz, CHD),
SmI2-promoted reduction in the presence of D2O provides a
rapid and efficient method for synthesizing aromatic or
aliphatic a-alkylated 2,3-dideuterio acids. Starting from
alka-2,4-dienoic acids, a,d-dideuterio-b,g-unsaturated acids
‡
29.8 (t, J ˆ 19.9 Hz, CHD); MS (70 eV): m/z (%): 198 (34) [M] , 138 (100);
HRMS: calcd for C10H10D2O4: 198.0859; found: 198.0875; IR (neat): nÄ ˆ
ˆ
were prepared, their new C C being generated with total
3421, 3055, 2939, 1706 cmÀ1; Rf ˆ 0.2 (hexane/AcOEt 1:1).
diastereoselectivity. When H2O was used instead of D2O,
saturated or b,g-unsaturated carboxylic acids were isolated.
The present method is easy, simple and rapid. In addition,
cheap D2O is used to obtain isotopically labeled compounds.
Mechanisms to explain these syntheses have been proposed.
Other isotopically labeled acids were also obtained.
2,3-Dideuterio-2-methyl-3-phenylpropionic acid (2e): 1H NMR (200 MHz,
CDCl3): d ˆ 11.40 (brs, 2H), 7.49 7.11 (m, 10H), 3.00 (brs, 1H), 2.71 (brs,
1H), 1.22 (s, 6H); 13C NMR (50 MHz, CDCl3): d ˆ 182.6 (C), 138.9 (C),
128.9 (CH), 128.3 (CH), 126.3 (CH), 40.7 (t, J ˆ 19.2 Hz, CD), 38.6 (t, J ˆ
‡
19.4 Hz, CHD), 16.2 (CH3); MS (70 eV): m/z (%): 166 (21) [M] , 92 (100),
73 (14); IR (neat): nÄ ˆ 3424, 3028, 2931, 1704 cmÀ1; Rf ˆ 0.4 (hexane/AcOEt
3:1).
1
3-Phenylpropionic acid (2 f): H NMR (200 MHz, CDCl3): d ˆ 10.92 (brs,
1H), 7.40 7.23 (m, 5H), 3.01 (t, J ˆ 7.72 Hz, 2H), 2.72 (t, J ˆ 7.72 Hz, 2H);
13C NMR (50 MHz, CDCl3): d ˆ 179.2 (C), 140.0 (C), 128.4 (CH), 128.1
(CH), 126.2 (CH), 35.5 (CH2), 30.4 (CH2); MS (70 eV): m/z (%): 150 (41)
Experimental Section
General: Reactions requiring an inert atmosphere were conducted under
dry nitrogen, and the glassware was oven dried (1208C). THF and diethyl
ether were distilled from sodium/benzophenone immediately prior to use.
All reagents were purchased from Aldrich or Merckand were used without
further purification. Samarium diiodide was prepared by reaction of CH2I2
with samarium powder.[20] Deuterium oxide minimun isotopic purity 99.95
atom% D was used. Silica gel for flash chromatography was purchased
from Merck(200 450 mesh), and compounds were visualized by thin-layer
chromatography on analytical silica gel coated aluminium plates using UV
light (254 nm). 1H NMR spectra were recorded at 200, 300, or 400 MHz.
13C NMR spectra and DEPT experiments were determined at 50 or
75 MHz. Chemical shifts are given in ppm relative to tetramethyl-
silane (TMS), which is used as an internal standard, and coupling constants
(J) are reported in Hz. GC-MS and HRMS were measured at 70 eVor using
FAB conditions. When HRMS could not be measured on molecular ion the
HRMS of a significant fragment is given. Only the most important IR
absortions (incmÀ1) and the molecular ions and/or base peaks in MS are
given.
‡
[M] , 104 (57), 90 (100); IR (neat): nÄ ˆ 3427, 3056, 2687, 1708 cmÀ1; Rf ˆ 0.3
(hexane/AcOEt 3:1).
2,3-Dideuteriosuccinic acid (2g): 1H NMR (300 MHz, [D6]DMSO): d ˆ
12.20 (brs, 4H), 2.51 (brs, 2H), 2.40 (brs, 2H); 13C NMR (75 MHz,
[D6]DMSO): d ˆ 173.9 (C), 28.7 (t, J ˆ 19.7 Hz, CHD); HRMS: calcd for
C4H4D2O4: 120.0390; found: 120.0394; IR (neat): nÄ ˆ 3424, 1652 cmÀ1; Rf ˆ
0.1 (hexane/AcOEt 1:1).
2,3-Dideuterio-2-methyldecanoic acid (2h): 1H NMR (300 MHz, CDCl3):
d ˆ 2.01 1.01 (m, 16H), 1.00 0.75 (m, 3H); 13C NMR (75 MHz, CDCl3):
d ˆ 182.8 (C), 38.8 (t, J ˆ 22.1 Hz, CD), 33.0 (t, J ˆ 18.9 Hz, CHD), 31.7
(CH2), 29.6 (CH2), 29.4 (CH2), 29.3 (CH2), 29.2 (CH2), 26.9 (CH2), 22.6
‡
(CH2), 16.6 (CH3), 14.0 (CH3); MS (70 eV): m/z (%): 188 (3) [M] , 88 (29),
75 (100); IR (neat): nÄ ˆ 3432, 2924, 2855, 1705 cmÀ1; Rf ˆ 0.3 (hexane/
AcOEt 5:1).
3-Cyclohexyl-2,3-dideuterio-2-methylpropionic acid (2i): 1H NMR
(200 MHz, CDCl3): d ˆ 2.05 0.84 (m, 12H), 1.16 (s, 3H); 13C NMR
(75 MHz, CDCl3): d ˆ 183.6 (C), 40.7 (t, J ˆ 19.2 Hz, CHD), 36.1 (t, J ˆ
20.4 Hz, CD), 35.0 (CH), 33.1 (CH2), 32.9 (CH2), 29.6 (CH2), 26.4 (CH2),
Synthesis of 2,3-dideuterated or saturated carboxylic acids 2 and prepara-
tion of (E)-2,5-dideuterio-b,g-unsaturated or (E)-b,g-unsaturated acids 8:
Under nitrogen, a solution of SmI2 (1.2 mmol) in THF (15 mL) was added
dropwise to a stirred solution of the appropriate acid 1 or 7 in D2O (2 mL)
and THF (2 mL) at room temperature. The reaction mixture was stirred for
30 min and then treated with 0.1m aqueous HCl (5 mL). Standard workup
afforded the crude dideuterio acids 2 or 8, which were purified by flash
column chromatography on silica gel (hexane/ethyl acetate 5:1).
‡
26.1 (CH2), 17.2 (CH3); MS (70 eV): m/z (%): 172 (2) [M] , 127 (35), 98
(100), 75 (61), 55 (48); HRMS: calcd for C10H16D2O2: 172.1430; found:
172.1438; IR (neat): nÄ ˆ 3408, 2923, 2852, 1704 cmÀ1; Rf ˆ 0.3 (hexane/
AcOEt 5:1).
(E)-2,5-Dideuteriopent-3-enoic acid (8a): 1H NMR (300 MHz, CDCl3):
d ˆ 10.65 (brs, 1H), 5.64 (dd, J ˆ 15.65, 5.09 Hz, 1H), 5.57 5.44 (m, 1H),
3.11 3.00 (brm, 1H), 1.82 1.60 (brm, 2H); 13C NMR (75 MHz, CDCl3):
d ˆ 178.7 (C), 130.0 (CH), 121.8 (CH), 37.4 (t, J ˆ 19.7 Hz, CHD), 17.5 (t,
If H2O was used instead of D2O, saturated acids or (E)-b,g-unsaturated
acids were obtained.
‡
J ˆ 19.5 Hz, CH2D); MS (70 eV): m/z (%): 102 (55) [M] , 84 (10), 57 (100);
1
2,3-Dideuterio-3-phenylpropionic acid (2a): H NMR (300 MHz, CDCl3):
IR (neat): nÄ ˆ 3418, 3013, 2922, 1707 cmÀ1; Rf ˆ 0.4 (hexane/AcOEt 3:1).
d ˆ 10.91 (brs, 1H), 7.40 7.23 (m, 5H), 3.00 (brd, J ˆ 7.69 Hz, 1H), 2.71
(brd, J ˆ 7.69 Hz, 1H); 13C NMR (75 MHz, CDCl3): d ˆ 179.2 (C), 140.0
(C), 128.4 (CH), 128.1 (CH), 126.2 (CH), 35.2 (t, J ˆ 19.5 Hz, CHD), 30.1 (t,
(E)-2,5-Dideuteriohex-3-enoic acid (8b): 1H NMR (300 MHz, CDCl3): d ˆ
10.46 (brs, 1H), 6.65 (dd, J ˆ 15.15, 5.28 Hz, 1H), 5.50 (dd, J ˆ 15.15,
5.87 Hz, 1H), 3.08 3.03 (m, 1H), 2.09 1.99 (m, 1H), 0.99 (d, J ˆ 7.44 Hz,
3H); 13C NMR (75 MHz, CDCl3): d ˆ 178.7 (C), 136.8 (CH), 119.7 (CH),
37.5 (t, J ˆ 19.5 Hz, CHD), 25.1 (t, J ˆ 19.4 Hz, CHD), 13.2 (CH3); MS
‡
J ˆ 19.8 Hz, CHD); MS (70 eV): m/z (%): 152 (43) [M] , 106 (49), 92 (100) ;
IR (neat): nÄ ˆ 3427, 3056, 2687, 1708 cmÀ1; Rf ˆ 0.3 (hexane/AcOEt 3:1).
2,3-Dideuterio-3-(4-hydroxyphenyl)propionic acid (2b): 1H NMR
(300 MHz, [D6]DMSO): d ˆ 7.09 (d, J ˆ 8.47 Hz, 2H), 6.76 (d, J ˆ
8.47 Hz, 2H), 2.76 (d, J ˆ 7.18 Hz, 1H), 2.53 (d, J ˆ 7.18 Hz, 1H);
13C NMR (75 MHz, [D6]DMSO): d ˆ 176.1 (C), 156.1 (C), 132.4 (C),
130.4 (CH), 116.3 (CH), 35.5 (t, J ˆ 18.7 Hz, CHD), 30.2 (t, J ˆ 17.0 Hz,
‡
(70 eV): m/z (%): 116 (63) [M] , 70 (63), 56 (100), 42 (85); HRMS: calcd for
C6H8D2O2: 116.0804; found: 116.0810; IR (neat): nÄ ˆ 3325, 2964, 1713 cmÀ1
;
Rf ˆ 0.5 (hexane/AcOEt 3:1).
(E)-Hex-3-enoic acid (8c): 1H NMR (200 MHz, CDCl3): d ˆ 11.04 (brs,
1H), 5.80 5.41 (m, 2H), 3.07 (d, J ˆ 6.26 Hz, 2H), 2.13 1.98 (m, 2H), 0.99
(t, J ˆ 7.44 Hz, 3H); 13C NMR (50 MHz, CDCl3): d ˆ 178.8 (C), 136.8 (CH),
‡
CHD); MS (70 eV): m/z (%): 168 (23) [M] , 108 (100), 78 (10); HRMS
calcd for C9H8D2O2: 168.0753; found: 168.0759; IR (neat): nÄ ˆ 3423, 3092,
2995, 1652 cmÀ1; Rf ˆ 0.3 (hexane/AcOEt 1:1).
119.7 (CH), 37.7 (CH2), 25.4 (CH2), 13.3 (CH3); MS (70 eV): m/z (%): 114
‡
2,3-Dideuterio-3-(3,4-dihydroxyphenyl)propionic acid (2c): 1H NMR
(300 MHz, D2O): d ˆ 6.78 (d, J ˆ 8.26 Hz, 1H), 6.71 (d, J ˆ 1.99 Hz, 1H),
(43) [M] , 68 (55), 55 (86), 41 (100); IR (neat): nÄ ˆ 3325, 2964, 1713 cmÀ1
;
Rf ˆ 0.5 (hexane/AcOEt 3:1).
4496
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0819-4496 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 19

Deuterated Carboxylic Salts
4493 4497
Synthesis of 3-deuterio acid 13e: Under nitrogen, a solution of compound
2e (0.4 mmol) in THF (4 mL) was added dropwise to a stirred solution of
lithium diisopropylamide (1.6 mmol) in THF (18 mL) at room temperature
and the reaction was allowed to proceed under reflux. After stirring for
30 min, the reaction mixture was quenched by the addition of H2O (5 mL).
Standard workup provided the 3-deuterio acid 13e which was purified by
flash column chromatography on silica gel (hexane/AcOEt 5:1).
[5] a) By using baker×s yeast reduction: G. Fronza, C. Fuganti, P.
Grasselli, A. Mele, A. Sarra, Tetrahedron Lett. 1993, 34, 6467 6470;
b) G. Fronza, C. Fuganti, M. Mendozza, R. Rigoni, S. Servi, G. Zuchi,
Pure Appl. Chem. 1996, 68, 2065 2071; c) by using reductasa: A. R.
Battersby, A. L. Gutman, C. J. R. Fookes, H. G¸nther, H. Simon, J.
Chem. Soc. Chem. Commun. 1981, 645 647; d) A. G‰bler, W. Boland,
U. Preiss, H. Simon, Helv. Chim. Acta 1991, 74, 1773 1789; e) M.
Veith, M. Lorenz, W. Boland, H. Simon, K. Dettner, Tetrahedron 1994,
50, 6859 6874; f) R. Eck, H. Simon, Tetrahedron 1994, 50, 13631
13640.
3-Deuterio-2-methyl-3-phenylpropionic acid (13e): 1H NMR (200 MHz,
CDCl3): d ˆ 10.07 (brs, 2H), 7.38 7.02 (m, 10H), 3.17 3.07 (m, 1H), 2.84
2.66 (m, 3H), 1.21 (d, J ˆ 6.65 Hz, 6H); 13C NMR (50 MHz, CDCl3): d ˆ
182.6 (C), 138.9 (C), 128.9 (CH), 128.3 (CH), 126.3 (CH), 40.7 (t, J ˆ
19.2 Hz, CD), 38.6 (t, J ˆ 19.4 Hz, CHD), 16.2 (CH3); MS (70 eV): m/z
[6] D. Schrˆder, H. Schwarz, J. Am. Chem. Soc. 1993, 115, 8818 8820.
[7] W. Leitner, J. M. Brown, H. Brunner, J. Am. Chem. Soc. 1993, 115,
152 159.
‡
(%): 165 (50) [M] , 118 (14), 92 (100), 66 (17); HRMS: calcd for
[8] A. Cabrera, H. Alper, Tetrahedron Lett. 1992, 33, 5007 5008.
[9] P. Girard, J. L. Namy, H. B. Kagan, J. Am. Chem. Soc. 1980, 102,
2693 2698.
[10] R. Yanada, K. Bessho, K. Yanada, Synlett 1995, 443 444.
[11] E. Hasegawa, D. P. Curran, J. Org. Chem. 1993, 58, 5008 5010.
C10H11DO2: 165.0899; found: 165.0901; IR (neat): nÄ ˆ 3424, 3028, 2931,
1704 cmÀ1; Rf ˆ 0.4 (hexane/AcOEt 3:1)
Synthesis of 2,5-dideuteriohexanoic acid (14b): 5% Rh/alumina (50 mg)
was added to a solution of compound 8b (0.4 mmol) in MeOH (25 mL).
The solution was stirred under H2 atmosphere for 12 h. The mixture was
filtered through Celite and washed with 0.1m HCl. Standard workup
provided the 2,5-dideuterio acid 14b which was purified by flash column
chromatography on silica gel (hexane/AcOEt 5:1).
¬
[12] J. M. Concellon, H. RodrÌguez-Solla, Chem. Eur. J. 2001, 7, 4266
4271.
¬
[13] J. M. Concellon, P. L. Bernad, H. RodrÌguez-Solla, Angew. Chem.
2001, 113, 4015 4017; Angew. Chem. Int. Ed. 2001, 40, 3897 3899.
[14] MS and HRMS spectra of compounds 2 and 8 show lackor very weak
2,5-Dideuteriohexanoic acid (14b): 1H NMR (300 MHz, CDCl3): d ˆ 11.13
(brs, 1H), 2.31 2.24 (m, 1H), 1.60 0.70 (m, 8H); 13C NMR (75 MHz,
CDCl3): d ˆ 180.5 (C), 33.7 (t, J ˆ 19.7 Hz, CHD), 31.0 (CH2), 24.2 (CH2),
21.8 (t, J ˆ 19.0 Hz, CHD), 13.6 (CH3); MS (70 eV): m/z (%): 118 (<1)
‡
peakof the [ M] of the corresponding non-deuterated compound,
indicating a presence of the non-deuterated compound <1%. A new
HRMS spectra of the methyl ester of 2a, obtained from 2a and
diazomethane, was carried out to avoid that the incorporation of
deuterium to the carboxylic group could maskthe HRMS spectra of
the dideuterated compounds 2 or 8. Moreover, to calculate the
incorporation of deuterium, HRMS spectra of compounds 2 and 8
have been compared with the corresponding non-deuterated products.
[15] a) M. Sefkow, A. Kelling, U. Schilde, Eur. J. Org. Chem. 2001, 2735
2742 and references therein; b) T. Chen, J. Li, J. Cao, Q. Xu, K.
Komatsu, T. Namba, Planta Med. 1999, 65, 56 59; c) T. Saito, H.
Yamane, N. Murofushi, N. Takahashi, B. O. Phinney, Biosci. Bio-
technol. Biochem. 1997, 61, 1397 1398; d) S. Dupre, M. Grenz, J.
Jakupovick, F. Bohlmann, H. M. Niemeyer, Phytochemistry 1991, 30,
‡
[M] , 88 (18), 74 (50), 61 (100), 42 (30); IR (neat): nÄ ˆ 3425,2993, 2822,
1705 cmÀ1; Rf ˆ 0.3 (hexane/AcOEt 5:1).
Acknowledgements
¬
We acknowledge financial support from III Plan Regional de Investigacion
del Principado de Asturias (PB-EXP01-11) and Ministerio de Ciencia y
¬
¬
TecnologÌa (BQU2001-3807). J.M.C. thanks Carmen Fernandez-Florez for
her time. H.R.S. thanks to Principado de Asturias for a predoctoral
fellowship. Our thanks to Robin Walker for revising the English manu-
script.
¬
¬
1211 1220; e) A. F. Barrero, J. F. Sanchez, E. J. R. Alvarez-Manza-
¬
neda, R. R. Alvarez-Manzaneda, Phytochemistry 1988, 27, 1191
1194.
[16] Y. Fujita, S. Fukuzumi, J. Otera, Tetrahedron Lett. 1997, 38, 2121
2124.
[17] To the best of our knowledge, the conjugated reduction of aliphatic
non-a-alkylated-b,g-unsaturated acids by using SmI2 has not been
described (see ref. [8]).
[1] I. Fleming, Comprehensive Organic Synthesis, Vol. 8, Pergamon Press,
Oxford, 1991, Chapter 3, pp. 417 792.
[2] J. Mann, Secondary Metabolism, Oxford University Press, Oxford,
1986, p. 23.
[3] For a review of the use of deuterium to study the mechanism of
heterogeneous organic catalysis, see: B. S. Gudkov, Russ. Chem. Rev.
1986, 55, 259 270.
[4] a) T. Ohta, H. Tayaka, R. Noyori, Tetrahedron Lett. 1990, 31, 7189
7192; b) M. Shaharuzzaman, J. Chickos, C. N. Tam, T. A. Keiderling,
Tetrahedron: Asymmetry 1995, 6, 2929 2932; c) J. Yu, J. B. Spencer,
Tetrahedron 1998, 54, 15821 15832.
ˆ
[18] A similar 1,4-reduction of conjugated bond C C has been described
from alkyl alka-2,4-dienoates (see ref. [13]).
[19] S. G. Davies, G. D. Smyth, Tetrahedron: Asymmetry 1996, 7, 1001
1004.
[20] J. L. Namy, P. Girard, H. B. Kagan, Nouv. J. Chem. 1981, 5, 479 484.
Received: May 10, 2002 [F4079]
Chem. Eur. J. 2002, 8, No. 19
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0819-4497 $ 20.00+.50/0
4497