Titanium-mediated addition of grignard reagents to acyl cyanohydrins: Aminocyclopropane versus 1,4-diketone formation

Article abstract of DOI:10.1002/ejoc.201301251

The 1,2-dianion reactivity of the reagent generated from EtMgBr and titanium isopropoxide was illustrated when N-acyl cyanohydrins were used as substrates (>20 examples), giving both aminocyclopropane derivatives and 1,4-dicarbonyl compounds. When the reaction was performed in diethyl ether, 5-hydroxy-1,4-diketones were the main product. Under specific conditions (use of tetrahydrofuran and a bulky carboxylic moiety), the cyclopropane derivatives were obtained in good yields. The observed dichotomy may be explained by a ring-opening of the five-membered titanacycle intermediate followed by a nonselective acyl addition. The 1,2-dianion reactivity of the reagent generated from EtMgBr and Ti(OiPr)₄ was illustrated when N-acyl cyanohydrins were used as substrates (>20 examples). When the reaction was performed in diethyl ether, 1,4-diketones were mainly isolated. Under certain conditions, cyclopropane derivatives were also obtained in good yields. A mechanism rationalizing this dichotomy is presented. Copyright

Full text of DOI:10.1002/ejoc.201301251

Job/Unit: O31251
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DOI: 10.1002/ejoc.201301251
Titanium-Mediated Addition of Grignard Reagents to Acyl Cyanohydrins:
Aminocyclopropane versus 1,4-Diketone Formation
Paul Setzer,[a] Gwénaël Forcher,[a] Fabien Boeda,[a] Morwenna S. M. Pearson-Long,[a] and
Philippe Bertus*[a]
Keywords: Grignard reaction / Ketones / Small ring systems / Solvent effects / Titanium
The 1,2-dianion reactivity of the reagent generated from
EtMgBr and titanium isopropoxide was illustrated when N-
acyl cyanohydrins were used as substrates (Ͼ20 examples),
giving both aminocyclopropane derivatives and 1,4-di-
carbonyl compounds. When the reaction was performed in
diethyl ether, 5-hydroxy-1,4-diketones were the main prod-
uct. Under specific conditions (use of tetrahydrofuran and a
bulky carboxylic moiety), the cyclopropane derivatives were
obtained in good yields. The observed dichotomy may be ex-
plained by a ring-opening of the five-membered titanacycle
intermediate followed by a nonselective acyl addition.
nitrogen atom leads to an iminium intermediate, which cy-
clizes to give tertiary cyclopropylamines.[4] In both cases,
the carboxylic acid derivative is the only electrophilic spe-
cies, and, since the five-membered metallacycles B1 or B2
are transient species, they cannot be used for other transfor-
mations involving the remaining Ti–C bond.
Introduction
Since their first use in 1989, dialkoxytitanacyclopropanes
A, also described as π-alkene complexes AЈ (Scheme 1),
have been developed as inexpensive and versatile reagents
for C–C bond formation, including cyclopropanation reac-
tions and reductive coupling of olefins, as described in sev-
eral reviews related to this topic.[1] These reagents are typi-
cally generated in the reaction media from titanium isopro-
poxide and organomagnesium halides by β-fragmentation
of the dialkylmetal intermediate, but were never isolated,
although the full characterization of related metallocene
complexes has been carried out.[2]
Scheme 1. Formation of titanacyclopropane A.
The 1,2-dianion reactivity of dialkoxytitanacyclopro-
panes is well-illustrated by their reaction with carboxylic
esters (the Kulinkovich reaction)[3] and amides [Scheme 2,
Equations (1) and (2)].[4] In both cases, a five-membered
metallacycle is involved, by insertion of the carbonyl moiety
into the titanium–carbon bond. With esters, the leaving
ability of the alkoxy group leads to the formation of tran-
sient homoenolate species, which spontaneously undergo
cyclization to furnish cyclopropanols after hydrolysis.[3,5]
From amides, however, the electron-donating ability of the
Scheme 2. Reactivity of A with acid derivatives.
On the other hand, the reaction of A with other acid
derivatives, including imides,[6] acylpyrroles[7] or simple ni-
triles[8] generally leads to the formation of stable five-mem-
bered metallacycles, in which the remaining metal–carbon
bonds could be cleaved by only a few reagents (H2O, D2O,
O2 or I2), limiting the synthetic use of these intermediates.
The cyclopropanation reaction may, however, be initiated
by the addition of Lewis acids as shown for nitriles
[Scheme 2, Equation (3)]. As a general point, carbon–metal
bonds in five-membered titanacycles are rather poorly nu-
[a] LUNAM Université, Université du Maine, CNRS UMR 6283,
Institut des Molécules et Matériaux du Mans (IMMM),
Avenue Olivier Messiaen, 72085 Le Mans Cedex 9, France
E-mail: philippe.bertus@univ-lemans.fr
http://immm.univ-lemans.fr/fr/equipes/mso.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301251.
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FULL PAPER
cleophilic, and, to the best of our knowledge, no intermo- skeleton, with varying degrees of generality, have been de-
lecular addition to carbonyl derivatives have been reported veloped.[12] The above preparation from acyl cyanohydrins
to date.[9] Although dialkoxytitanacyclopropanes A are eas- would represent a competitive, convenient access to this
ily accessible 1,2-dianion equivalents, their synthetic use kind of compounds, and preliminary results were recently
with two distinct electrophiles is somewhat limited, and ef- presented.[13] In this paper, the dual 1,2-dianion reactivity
forts are required to overcome this restriction.
of dialkoxytitanacyclopropanes with acyl cyanohydrins is
As part of a project devoted to the synthesis of substi- described, underlining the factors governing the divergent
tuted aminocyclopropanecarboxylic acid derivatives from formation of diketones versus cyclopropanes, which will be
nitriles,[10] we have studied the titanium-mediated cyclopro- rationalized in a proposed mechanism.
panation of cyanocarbonates 1. The oxazolidinone 2 and/
or amino alcohol 3 were obtained depending on the substi-
tution of the starting material [Scheme 3, Equation (a)].[11]
Based on the results obtained with cyano ester 4, which give
only spirocyclopropane lactam 5 in high yield [Equa-
tion (b)], we expected that the use of acyl cyanohydrins 6
would lead exclusively to the formation of cyclopropane de-
rivatives 7 by cyclopropylamine formation and subsequent
acyl transfer, by a pathway similar to that leading to 3
[Equation (c)].
Results and Discussion
Experimental conditions favoring the formation of either
cyclopropane 7 or diketone 8 were examined with cya-
nomethyl benzoate 6a as starting material (obtained in one
step from benzoic acid and chloroacetonitrile).[14] When 6a
was allowed to react at room temperature with ethylmagne-
sium bromide (2 equiv.) and titanium isopropoxide
(1.1 equiv.) in Et2O (Table 1), four compounds were ob-
served after hydrolysis and NMR analysis of the crude ma-
terial (Scheme 5). The main product was diketone 8a
(60%), with the expected cyclopropylamine 7a being ob-
tained in only 9% yield. The two other compounds also
observed in minor amounts were oxo ester 9a, resulting
from direct addition of the Grignard reagent to the cyano
ester,[15] and isopropyl benzoate (10a), obtained from the
reaction of 6a with Ti(OiPr)4 alone.[16,17]
Scheme 3. Reactivity of cyano esters and cyano carbonates with
EtMgBr/Ti(OiPr)4.
Preliminary experiments have established that the reac-
tion of cyanomethyl benzoate (6a) under cyclopropanation
conditions [addition of EtMgBr to a solution of Ti(OiPr)4
in Et2O at room temp.] led mainly to 5-hydroxy-1-phenyl-
pentane-1,4-dione (8a) instead of the expected cyclopropyl-
amine derivative 7a, the latter being obtained only in low
yield (Scheme 4). The formation of 1,4-dicarbonyl com-
pound 8a apparently originates from a double nucleophilic
addition of the titanacyclopropane onto both nitrile and
ester moieties.
Scheme 5. Products resulting from the reaction of 6a and EtMgBr/
Ti(OiPr)4.
To determine the parameters influencing the 7a/8a ratio
and to maximize the yield of 8a, optimization of the reac-
tion conditions were carried out; the main results are sum-
marized in Table 1.
When the reaction was carried out in Et2O at room
temp., diketone 8a was isolated in 56% yield (Table 1, En-
try 1). Lowering of the amount of titanium isoproproxide
to 0.2 equiv. revealed that a substoichiometric amount of
titanium reagent could be used, with an increase of the 7a/
8a ratio (1:3.8 vs. 1:6.7); however, this led to a lower yield
(Entry 2). Owing the relatively low cost of titanium isopro-
poxide, subsequent reactions were performed with stoichio-
metric amounts of the reagent. The conditions for the for-
mation of 8a were slightly improved by mixing the reagents
at 0 °C and subsequent warming to room temperature (En-
Scheme 4. Unexpected formation of 8a from 6a.
Because 1,4-diketones are valuable building blocks for try 3). The use of 3 equiv. EtMgBr did not affect the reac-
the synthesis of cyclopentenones and five-membered het- tion outcome (Entries 4 vs. 3), indicating that no free carb-
erocyclic compounds, several synthetic approaches to this onyl group is present in the intermediate leading to 8a after
2
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Ti-Mediated Addition of Grignard Reagents to Acyl Cyanohydrins
Table 1. Parameters governing the formation of 7a and/or 8a.
Entry
Conditions[a]
Yield [%][b]
8a
7a
9a
10a
1
2
3
4
5
6
7
8
9
Ti(OiPr)4 (1.1), EtMgBr (2.1), Et2O, r.t., 1 h
Ti(OiPr)4 (0.2), EtMgBr (2), Et2O, r.t., 1 h
Ti(OiPr)4 (1.1), EtMgBr (2.1), Et2O, 0 °C to r.t., 1 h
Ti(OiPr)4 (1.1), EtMgBr (3), Et2O, r.t., 1 h
Ti(OiPr)4 (1.1), EtMgBr (1.5), Et2O, r.t., 1 h
Ti(OiPr)4 (1.1), EtMgBr (2.1), toluene, r.t., 1 h
Ti(OiPr)4 (1.1), EtMgBr (2.1), CH2Cl2, r.t., 1 h
Ti(OiPr)4 (1.1), EtMgBr (2.1), THF, r.t., 1 h
MeTi(OiPr)3 (1.1), EtMgBr (1.5), Et2O, r.t., 1 h
Cp2ZrCl2 (1.1), EtMgBr (2.1), THF, r.t., 1 h
EtMgBr (2.1), Et2O, r.t., 1 h
9
12
5
6
3
12
9
28
8
0
0
60 (56)
45
71 (69)
70 (68)
17[c]
65
71 (68)
48
9
2
0
0
7
9
3
0
0
3
0
0
0
3
2
2
0
8
0
0
70 (65)
44
10
11
0
[d]
0
1
[a] Reactions performed on a 1 mmol scale. [b] Yields estimated from H NMR analysis of the crude material after extraction. Isolated
yields given in parentheses. [c] Starting nitrile 6a was also observed (53%). [d] Products derived from the addition of EtMgBr to 6a were
obtained, see text and Scheme 6.
hydrolysis. On the other hand, reducing the amount of the nature of substituents in the para or meta position did
Grignard reagent reduced the conversion dramatically, not significantly alter the yield or ratio of 7/8 (Entries 3–6).
clearly showing the need for at least 2 equiv. EtMgBr (En- In contrast, the presence of a substituent in the ortho posi-
try 5). Other solvents were evaluated. Toluene or CH2Cl2 tion slightly increased the amount of cyclopropane formed
gave results similar to that when using Et2O (Entries 6 and (Entry 7 vs. 1). This effect is more pronounced in THF, in
7), whereas in tetrahydrofuran (THF) the 7a/8a ratio was which cyclopropane 7f was formed as the major product
modified in favor of the formation of the cyclopropane (Entries 8 vs. 7). A very similar trend was observed with
(1:1.7; Entry 8), with diketone 8a remaining the main prod- naphthyl derivatives 6g and 6h (Entries 9–11), leading to a
uct. Changing the titanium complex to MeTi(OiPr)3 did higher 7/8 ratio with the more crowded 1-naphthyl deriva-
not significantly modify the reaction profile (Entry 9). The tive. The reaction works well with linear, branched, or cyclic
reaction was also performed by using Cp2ZrCl2 instead of aliphatic cyano esters (Entries 12–19). Here also, the extent
Ti(OiPr)4; whereas in Et2O or in CH2Cl2 no trace of 7a or of crowding around the ester moiety is of importance. From
8a was observed with this reagent, when the reaction was linear cyanomethyl butyrate (6i), hydroxy diketone 8i was
performed in THF, formation of diketone 8a occurred with- obtained as the main product, regardless of the solvent used
out any trace of cyclopropane (Entry 10), albeit in moder- (Entries 12 and 13). In contrast, from cyanomethyl pivalate
ate yield due to the formation of a considerable amount of (6l) a dramatic reversal of chemoselectivity was observed;
byproducts. Finally, only alkylation products 11a and 12a in Et2O, product 8l was mainly obtained (Entry 16),
were obtained when the reaction was undertaken without whereas in THF cyclopropane derivative 7l was formed as
titanium catalyst (Entry 11 and Scheme 6). Alcohol 11a was the major product (Entry 17). The same results were ob-
obtained from classical double addition to the ester moiety, served from 1-adamantyl derivatives (Entries 18 and 19).
and 12a would result from twofold addition of Grignard Unsaturated substrates were also well tolerated (Entries 20–
reagent to the nitrile moiety and O,N-acyl migration.[18]
23), although unsaturated esters were prone to side-reac-
tions in Ti-mediated cyclopropanation of carboxylic es-
ters.[19] The use of heterocycles as substrates was then
checked, with 2-furyl and 2-thienyl derivatives giving fair to
good yields (Entries 24 and 25). In contrast, cyanomethyl
picolinate (6t) did not give any trace of 7 or 8; in this case,
only isopropyl picolinate was observed (Entry 26), deriving
from the unusually fast and quantitative transesterification,
mediated by Ti(OiPr)4 alone (Scheme 7).[16,17]
Scheme 6. Addition of EtMgBr to 6a.
With the best conditions for the formation of hydroxy
diketone 8 established, a series of cyano esters 6a–w and
some related analogues 6x–y were used to evaluate the
Substitution in the α position of the nitrile did not affect
scope and limitations of this reaction. Because the nature of the outcome of the reaction (Table 2, Entries 27–30), giving
the solvent plays a significant role in the 7/8 ratio, selected access to compounds bearing a 1,5-disubstituted 5-hydroxy-
reactions were performed both in Et2O and in THF. The 1,4-diketone framework. Finally, to study the reactivity of
results are presented in Table 2.
related substrates, a cyano carbamate (6x) and a cyano car-
First, with all the cyanomethyl carboxylates 6a–w bonate (6y) were submitted to the same reaction conditions.
studied, the amount of hydroxydiketone 8 formed was al- From the cyano carbamate (Entries 31 and 32), an equi-
ways significantly higher than the amount of cyclopropane molar mixture of oxo amide and cyclopropylurea deriva-
7 when the reaction was carried out in Et2O (from 70:30 to tives was obtained regardless of the solvent used. From cy-
97:3), indicating that this is a reaction of synthetic interest. ano carbonate 6y (Entry 33), as shown by previous studies
Aryl groups were well-tolerated (Table 2, Entries 1–11), and (Scheme 3),[10c,20] no trace of oxo ester was observed, and
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Table 2. Titanium-mediated addition of EtMgBr to nitriles 6a–y.
Entry
R
RЈ
Solvent
7/8 ratio[a]
Product (yield, %)[b]
8a (69)
1
2
3
4
5
6
7
8
Ph (6a)
Ph (6a)
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Ph
Me
H
H
H
Et2O
THF
Et2O
Et2O
Et2O
Et2O
Et2O
THF
Et2O
Et2O
THF
Et2O
THF
Et2O
Et2O
Et2O
THF
Et2O
THF
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
THF
Et2O
Et2O
Et2O
THF
Et2O
14:86
37:63
13:87
7:93
8:92
7:93
20:80
60:40
7:93
22:78
59:41
7:93
13:87
13:87
8:92
20:80
90:10
30:70
81:19
12:88
3:97
7a (25)
8a (45)
8b (65)
8c (60)
8d (60)
8e (74)
8f (62)
8f (31)
8g (62)
8h (66)
8h (32)
8i (50)
8i (48)
8j (50)
8k (55)
8l (56)
pMeOC6H4 (6b)
pFC6H4 (6c)
pBrC6H4 (6d)
mBrC6H4 (6e)
oBrC6H4 (6f)
oBrC6H4 (6f)
2-naphthyl (6g)
1-naphthyl (6h)
1-naphthyl (6h)
nPr (6i)
7f (40)
7h (40)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
nPr (6i)
iBu (6j)
cyclopropyl (6k)
tBu (6l)
tBu (6l)
7l (60)
1-adamantyl (6m)
1-adamantyl (6m)
H2C=CH(CH2)8 (6n)
H3CCH=CH (6o)
PhCH=CH (6p)
PhCϵC (6q)
2-furyl (6r)
8m (58)
7m (69)
8n (62)
8o (42)
8p (45)
8q (42)
8r (50)
8s (65)
8t (0)
8:92
22:78
12:88
2-thienyl (6s)
2-pyridyl (6t)
Ph (6u)
Ph (6u)
Ph (6v)
pBrC6H4 (6w)
Ph2N (6x)
19:81
[c]
15:85
28:72
22:78
12:88
54:46
57:43
100:0
8u (56)
8u (52)
8v (52)
8w (50)
8x (34)
8x (27)
7u (9)
7x (40)[d]
7x (36)[d]
Ph2N (6x)
EtO (6y)
2 (30) + 7y (31)[e]
[a] The 7/8 ratio was determined by 1H NMR spectroscopic analysis of the crude material. [b] Isolated yield after purification by
chromatography. [c] Only the formation of isopropyl picolinate was observed. [d] Compound 7x was contaminated with traces of an
aromatic compound. [e] 6-Oxa-4-azaspiro[2.4]heptan-5-one (2; 30%) was obtained together with 7y (31%).
Table 3. Titanium-mediated addition of EtMgBr to 3-acyloxypro-
pionitrile derivatives 13a–c.
Scheme 7. Transesterification of 6t mediated by Ti(OiPr)4.
only the cyclopropane derivatives 7y and 2 were ob-
tained.[21] On the basis of these experiments, the ease of
formation of dicarbonyl compound 8 seems to decrease
from ester to carbamate and finally carbonate in this reac-
tion.
Cyano esters 13a–c, derived from ethylene cyanohydrin,
were then used to evaluate the effect of the distance between
the nitrile and the ester moiety (Table 3). In the three cases
studied, an increase in the cyclopropane/diketone ratio sim-
ilar to those of the respective acyl cyanohydrins was ob-
Entry
R
Solvent 14/15 ratio[a] Products (yield [%])[b]
1
2
3
4
5
6
Ph (13a)
Ph (13a)
Et (13b)
Et (13b)
tBu (13c) Et2O
tBu (13c) THF
Et2O
THF
Et2O
THF
70:30
81:19
55:45
40: 60
100:0
100:0
14a (50)
14a (41)
14b (24)
14b (19)
14c (57)
14c (59)
15a (24)
15b (32)
15b (19)
[a] The 14/15 ratio determined from 1H NMR spectroscopic analy-
sis of the crude material. [b] Isolated yield after chromatography
served (Table 2). In the extreme case of pivalate ester 13c, purification.
4
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Ti-Mediated Addition of Grignard Reagents to Acyl Cyanohydrins
no trace of dicarbonyl compound was found, and only cy- try 4). Alternatively [Path (b)], addition to the imine can
clopropane derivative 14c was obtained, providing potential lead to the formation of dimetallated amine G, which un-
access to β-amino acid derivatives bearing a cyclopropane dergoes subsequent acyl transfer to afford cyclopropyl-
moiety.
amine derivative 7 after hydrolysis. This proposition shows
To gain a better insight into the reaction mechanism, a the divergent synthesis of 7 and 8 from a common interme-
1:1 mixture of cyanohydrins 6d/6u was subjected to the re- diate E. On the basis of the results collected in Tables 2 and
action conditions. As shown in Scheme 8, only diketones 8d 3, the formation of 8 is highly favored when the carbonyl
and 8u, resulting from their respective cyano esters, were group is not crowded and in adequate distance from the
obtained, without any trace of cross products. This result nitrile (easy to form the six-membered intermediate F).
clearly indicates an intramolecular process (i.e., the acyl and When the electrophilicity of the carbonyl moiety decreases
hydroxy ketone parts stem from the same molecule) and (aliphatic vs. aromatic, or increased crowding, or carbamate
rules out the possible involvement of two molecules of cy- vs. ester), Path (a) is less efficient, and Path (b) becomes fa-
ano esters in the reaction mechanism.
vored, giving the cyclopropylamine derivative. This effect is
more pronounced in THF than in Et2O, as exemplified by
the divergent synthesis of 7l or 8l (Table 2, Entries 16 and
17). Additionally, increasing the distance of the ester moiety
disfavors the formation of F (seven-membered intermediate
in this case), and thus increases the amount of cyclopro-
pane formed (Table 3).
Scheme 8. Competitive synthesis of γ-diketones from a mixture of
6d and 6u.
In the light of the above experimental results, a tentative
mechanism is depicted in Scheme 9. The first step would
imply the insertion of the nitrile moiety of cyano ester 6
into titanacyclopropane intermediate A [generated in situ
from Ti(OiPr)4 and 2 equiv. EtMgBr] to provide five-mem-
bered titanacycle C. The insertion reaction is totally re-
gioselective here, because cyclopropanol 16 (resulting from
a
Kulinkovich reaction) has never been observed
(Scheme 9).[22] Diketone 8 might be directly obtained from
an intramolecular direct insertion of the ester C=O func-
tionality into the remaining titanium–carbon bond; how-
ever, this possibility is highly improbable due to clear geo-
metric constriction of intermediate D (Bredt’s rule viola-
tion). An alternative and more plausible pathway would in-
volve a C,N-dimetallated intermediate such as E,[23] which
results from ring-opening of C by magnesium alkoxides or
Grignard reagents. Such Grignard-mediated metallacycle
ring openings have already been proposed for related
mechanisms. For instance, the ring opening of five-mem-
bered oxatitanacyclopentanes has been proposed by Kulin-
kovich et al. to explain the excess of Grignard reagent re-
quired in the synthesis of cyclopropanols.[5c,24] Moreover,
Scheme 9. Mechanism for the dual formation of 7 and 8 from 6.
From a mechanistic point of view, the Ti-mediated reac-
the Cp2ZrCl2-catalyzed carbomagnesation of alkenes[25] or tion of cyano esters gives new information about the
imines[26] involves a Grignard-mediated zirconacyclopen- mechanism of the Ti-mediated cyclopropanation of ali-
tane ring-opening step in its catalytic cycle. From the di- phatic or aromatic nitriles. It is indeed highly plausible that
metallated intermediate E, two pathways may operate, de- the cyclopropanation occurs through ring opening of titan-
pending on the accessibility of the two electrophilic sites acycle B3, followed by ring closure by addition to metall-
(the metallated imine and the ester moieties). Following ated imine B4 (Scheme 10),[27,28] and not by a simple ring
Path (a), the addition occurs on the ester moiety giving a contraction, as generally shown (Scheme 2).[29] The lithium
stable six-membered intermediate F, which can be seen as a salts[30] or Lewis acids,[8,29] which are known to favor the
protected form of the hydroxy diketone 8, since it is not cyclopropanation of nitriles, may have an influence in the
affected by an excess of Grignard reagent (see Table 1, En- ring opening of metallacycle B3.
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0:100) afforded 8a (86 mg, 45%), followed by 7a (48 mg, 25%) as
a beige solid. M.p. 95 °C. IR (film): ν = 3067, 2959, 1726, 1651,
˜
1600, 1587, 1453, 1259, 1092 cm–1. 1H NMR (200 MHz, CDCl3):
δ = 7.79–7.64 (m, 2 H), 7.51–7.26 (m, 3 H), 4.55 (br., 1 H), 3.67
(d, J = 19.9 Hz, 1 H), 3.57 (d, J = 19.9 Hz, 1 H), 0.93 (d, J =
19.9 Hz, 2 H), 0.83 (d, J = 19.9 Hz, 2 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 170.3, 133.8, 131.8, 128.7, 127.2, 68.9, 35.9, 12.6 ppm.
HRMS (CI, NH3): calcd. for C11H14NO2 [M + H]+ 192.1025;
found 192.1031.
Scheme 10. Nitrile cyclopropanation reaction through metallacycle
ring opening.
5-Hydroxy-1-phenylpentane-1,4-dione (8a): According to the gene-
ral procedure, cyanomethyl benzoate (6a; 161 mg, 1 mmol) was
used; the reaction was performed in Et2O. After work-up, flash
column chromatography (silica gel; cyclohexane/EtOAc, 50:50) af-
forded 8a (133 mg, 69%) as a light-pink solid. M.p. 84 °C. IR
Conclusions
We have reported a simple preparation of 1,4-diketone
derivatives from inexpensive and readily available acyl cya-
nohydrins, titanium isopropoxide and ethylmagnesium
bromide. This reaction illustrates a new reactivity of titana-
cyclopropanes as 1,2-dianion equivalents. In addition, un-
der specific conditions (solvent, steric effects), the reaction
can be modulated to afford mainly aminocyclopropane de-
rivatives, and this dual reactivity was rationalized mechan-
istically. We are working on the development of the 1,2-
dianionic reactivity of titanacyclopropane to other sub-
strates.
(film): ν = 3428, 1723, 1681, 1212, 1013 cm–1. 1H NMR (200 MHz,
˜
CDCl3): δ = 7.98–7.94 (m, 2 H), 7.58 (tt, J = 7.4, 1.6 Hz, 1 H),
7.52–7.40 (m, 2 H), 4.41 (d, J = 3.6 Hz, 2 H), 3.40 (t, J = 6.2 Hz,
2 H), 3.06 (t, J = 4.4 Hz, 1 H), 2.81 (t, J = 6.2 Hz, 2 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 208.9, 198.1, 136.4, 133.5, 128.8,
128.2, 68.5, 32.6, 32.1 ppm. HRMS (CI, NH3): calcd. for C11H13O3
[M + H]+ 193.0865; found 193.0859.
5-Hydroxy-1-(4-methoxyphenyl)pentane-1,4-dione (8b): According
to the general procedure, cyanomethyl 4-methoxybenzoate (6b;
191 mg, 1 mmol) was used; the reaction was performed in Et2O.
After work-up, flash column chromatography (silica gel; cyclohex-
Experimental Section
ane/EtOAc, 50:50) afforded 8b (144 mg, 65%) as a white solid. M.p.
1
94 °C. IR (film): ν = 3497, 1708, 1663, 1017, 828 cm–1. H NMR
˜
General Remarks: All air- and moisture-sensitive manipulations
were carried out by using standard Schlenk techniques under ar-
gon. Et2O and THF were purified by passing through neutral alu-
mina columns under nitrogen. The Grignard reagents were pre-
pared in anhydrous Et2O by using conventional methods from the
appropriate bromide precursors and Mg turnings. Analytical TLC
was performed on Alugram SIL G/UV254 silica gel sheets (Mach-
erey–Nagel) with detection by staining with vanillin solution. Col-
umn chromatography was carried out using silica gel 60 (0.040–
0.063 mm) from Merck. Melting points were determined with a
(200 MHz, CDCl3): δ = 7.95 (d, J = 9.0 Hz, 2 H), 6.94 (d, J =
9.0 Hz, 2 H), 4.42 (d, J = 3.3 Hz, 2 H), 3.87 (s, 3 H), 3.37 (t, J =
6.2 Hz, 2 H), 3.06 (t, J = 3.9 Hz, 1 H), 2.79 (t, J = 6.2 Hz, 2 H)
ppm. 13C NMR (50 MHz, CDCl3): δ = 209.1, 196.6, 163.9, 130.5,
129.5, 114.0, 68.5, 55.6, 32.3, 32.2 ppm. HRMS (CI, NH3): calcd.
for C12H15O3 [M + H]+ 223.0970; found 223.0981.
1-(4-Fluorophenyl)-5-hydroxypentane-1,4-dione (8c): According to
the general procedure, cyanomethyl 4-fluorobenzoate (6c; 179 mg,
1 mmol) was used; the reaction was performed in Et2O. After work-
up, flash column chromatography (silica gel; cyclohexane/EtOAc,
70:30) afforded 8c (126 mg, 60%) as a white solid. M.p. 83 °C. IR
1
Büchi B-540 melting-point apparatus and are uncorrected. H and
13C NMR spectra were recorded with a Bruker DPX-200 or a
Bruker AC-400 spectrometer. Chemical shifts (δ) are expressed in
ppm units relative to the residual solvent peak. Coupling constants
are given in Hz. The multiplicities are reported as follows: singlet
(s), doublet (d), triplet (t), quadruplet (q), multiplet (m), and broad
signal (br.). IR spectra were obtained with a Perkin–Elmer Spec-
trum One spectrometer equipped with a single-reflection diamond
ATR unit. High-resolution mass spectra were recorded with a
Waters Micromass GCT Premier spectrometer. Compounds 2, 6y
and 7y were previously described.[20b]
(film): ν = 3415, 1716, 1678, 1160, 1013, 812 cm–1. 1H NMR
˜
(200 MHz, CDCl3): δ = 8.05–7.95 (m, 2 H), 7.20–7.08 (m, 2 H),
4.42 (d, J = 3.8 Hz, 2 H), 3.38 (t, J = 6.2 Hz, 2 H), 3.04 (t, J =
4.8 Hz, 1 H), 2.81 (t, J = 6.2 Hz, 2 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 208.9, 196.5, 165.9 (d, JC–F = 255 Hz), 132.8, 130.8
(d, JC–F = 9 Hz), 115.8 (d, JC–F = 22 Hz), 68.3, 32.3, 31.9 ppm. 19
F
NMR (400 MHz, CDCl3): δ = –105.6 ppm. HRMS (CI, NH3):
calcd. for C11H12FO3 [M + H]+ 211.0770; found 211.0766.
1-(4-Bromophenyl)-5-hydroxypentane-1,4-dione (8d): According to
the general procedure, cyanomethyl 4-bromobenzoate (6d; 240 mg,
1 mmol) was used; the reaction was performed in Et2O. After work-
up, flash column chromatography (silica gel; cyclohexane/EtOAc,
60:40) afforded 8d (163 mg, 60%) as a white solid. M.p. 121 °C. IR
General Procedure: To a solution of the nitrile (1 mmol) and
Ti(OiPr)4 (330 μL, 1.1 mmol) in Et2O or THF (10 mL) under argon
was added dropwise at 0 °C a solution of EtMgBr (ca. 1 m in Et2O,
2.1 mmol). Upon completion of the addition, the mixture was
warmed to room temp. and stirred for 2 h. Water (5 mL) was
added, followed by EtOAc (10 mL) and 1 m HCl until two clear
phases were obtained. The organic phase was separated and the
aqueous phase was extracted with EtOAc (2ϫ 20 mL). The com-
bined organic phases were washed with saturated aq. NaHCO3,
dried (MgSO4), and concentrated. The resulting oil was purified by
chromatography.
(film): ν = 3415, 1716, 1678, 1068, 807, 638 cm–1. 1H NMR
˜
(200 MHz, CDCl3): δ = 7.86–7.80 (m, 2 H), 7.68–7.64 (m, 2 H),
4.41 (d, J = 4.2 Hz, 2 H), 3.36 (t, J = 6.2 Hz, 2 H), 3.03 (t, J =
4.6 Hz, 1 H), 2.81 (t, J = 6.2 Hz, 2 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 208.7, 197.0, 135.1, 132.1, 129.6, 128.7, 68.4, 32.4,
32.0 ppm. HRMS (CI, NH3): calcd. for C11H12BrO3 [M + H]+
270.9970; found 270.9972.
N-[1-(Hydroxymethyl)cyclopropyl]benzamide (7a): According to the
general procedure, cyanomethyl benzoate (6a; 161 mg, 1 mmol) was
used; the reaction was performed in THF. After work-up, flash
column chromatography (silica gel; cyclohexane/EtOAc, 50:50 then
1-(3-Bromophenyl)-5-hydroxypentane-1,4-dione (8e): According to
the general procedure, cyanomethyl 3-bromobenzoate (6e; 240 mg,
1 mmol) was used; the reaction was performed in Et2O. After work-
up, flash column chromatography (silica gel; cyclohexane/EtOAc,
6
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O31251
/KAP1
Date: 28-10-13 17:45:21
Pages: 11
Ti-Mediated Addition of Grignard Reagents to Acyl Cyanohydrins
70:30) afforded 8e (200 mg, 74%) as a white solid. M.p. 107 °C. IR
IR (film): ν = 3485, 2918, 1708, 1661, 1506, 1367, 1268, 1068,
˜
1
(film): ν = 3424, 2916, 1715, 1682, 1563, 1419, 1206, 1024,
769 cm–1. H NMR (200 MHz, CDCl3): δ = 8.57 (d, J = 8.3 Hz, 1
˜
1
789 cm–1. H NMR (200 MHz, CDCl3): δ = 8.09 (t, J = 1.8 Hz, 1
H), 8.01–7.88 (m, 2 H), 7.85 (d, J = 7.6 Hz, 1 H), 7.65–7.39 (m, 3
H), 4.41 (s, 2 H), 3.40 (t, J = 6.1 Hz, 2 H), 3.27 (s, 1 H), 2.81 (t, J
= 6.1 Hz, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 208.8, 202.0,
H), 7.89 (ddd, J = 7.8, 1.8, 1.2 Hz, 1 H), 7.71 (ddd, J = 7.8, 1.8,
1.2 Hz,1 H), 7.36 (t, J = 7.8 Hz, 1 H), 4.41 (s, 2 H), 3.37 (t, J =
6.1 Hz, 2 H), 3.11 (br., 1 H), 2.81 (t, J = 6.1 Hz, 2 H) ppm. 13C 135.1, 134.0, 133.1, 130.1, 128.5, 128.1, 127.9, 126.6, 125.7, 124.4,
NMR (50 MHz, CDCl3): δ = 208.6, 196.8, 138.0, 136.3, 131.2,
130.4, 126.7, 123.1, 68.4, 32.5, 31.9 ppm. HRMS (ESI): calcd. for
C11H12BrO3 [M + H] 270.9964; found 270.9964.
68.4, 35.6, 32.4 ppm. HRMS (ESI): calcd. for C15H15O3 [M + H]
243.1016; found 243.1017.
1-Hydroxyoctane-2,5-dione (8i): According to the general pro-
cedure, cyanomethyl butanoate (6i; 127 mg, 1 mmol) was used; the
reaction was performed in Et2O. After work-up, flash column
chromatography (silica gel; cyclohexane/EtOAc, 70:30) afforded 8i
2-Bromo-N-[1-(hydroxymethyl)cyclopropyl]benzamide (7f): Accord-
ing to the general procedure, cyanomethyl 2-bromobenzoate (6f;
240 mg, 1 mmol) was used; the reaction was performed in THF.
After work-up, flash column chromatography (silica gel; EtOAc)
afforded 8f (84 mg, 31%), followed by 7f (108 mg, 40%) as a white
(79 mg, 50%) as a pale-yellow oil. IR (film): ν = 3456, 2962, 1706,
˜
1
1404, 1366, 1125, 1039, 986 cm–1. H NMR (200 MHz, CDCl3): δ
solid. M.p. 134 °C. IR (film): ν = 3225, 2923, 1638, 1555, 1424,
˜
= 4.34 (s, 2 H), 3.13 (s, 1 H), 2.81 (dd, J = 7.5, 5.4 Hz, 2 H), 2.64
(dd, J = 7.5, 5.4 Hz, 2 H), 2.44 (t, J = 7.3 Hz, 2 H), 1.75–1.48 (m,
2 H), 0.92 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3):
δ = 209.2, 208.8, 68.3, 44.6, 36.1, 31.8, 17.4, 13.8 ppm. HRMS (CI,
NH3): calcd. for C8H15O3 [M + H]+ 159.1021; found 159.1020.
1
1352, 1032, 725 cm–1. H NMR (200 MHz, CDCl3): δ = 7.57–7.45
(m, 2 H), 7.37–7.21 (m, 2 H), 6.75 (br., 1 H), 3.95 (br., 1 H), 3.67
(s, 2 H), 0.97 (m, 4 H) ppm. 13C NMR (50 MHz, CDCl3): δ =
170.4, 137.1, 133.4, 131.6, 129.6, 127.7, 119.4, 69.2, 36.2, 12.8 ppm.
HRMS (CI, NH3): calcd. for C11H13BrNO2 [M + H]+ 270.0128;
found 270.0130.
1-Hydroxy-7-methyloctane-2,5-dione (8j): According to the general
procedure, cyanomethyl 3-methylbutanoate (6j; 141 mg, 1 mmol)
was used; the reaction was performed in Et2O. After work-up, flash
column chromatography (silica gel; cyclohexane/EtOAc, 50:50) af-
1-(2-Bromophenyl)-5-hydroxypentane-1,4-dione (8f): According to
the general procedure, cyanomethyl 2-bromobenzoate (6f; 240 mg,
1 mmol) was used; the reaction was performed in Et2O. After work-
up, flash column chromatography (silica gel; cyclohexane/EtOAc,
forded 8j (86 mg, 50%) as a colorless liquid. IR (film): ν = 3466,
˜
1
1706, 1366, 1047 cm–1. H NMR (200 MHz, CDCl3): δ = 4.32 (s,
70:30) afforded 8f (168 mg, 62%) as a pale-yellow oil. IR (film): ν
˜
2 H), 3.03 (br., 1 H), 2.79 (t, J = 6.3 Hz, 2 H), 2.60 (t, J = 6.3 Hz,
2 H), 2.32 (d, J = 6.7 Hz, 2 H), 2.23–2.02 (m, 1 H), 0.90 (d, J =
6.7 Hz, 6 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 208.9, 208.9,
68.0, 51.3, 36.4, 31.5, 24.6, 22.3 ppm. HRMS (CI, NH3): calcd. for
C9H17O3 [M + H]+ 173.1178; found 173.1178.
= 3467, 3062, 2916, 1697, 1586, 1563, 1466, 1427, 1396, 1353, 1208,
1
1027, 1006 cm–1. H NMR (200 MHz, CDCl3): δ = 7.62 (dd, J =
7.7, 1.4 Hz, 1 H), 7.50 (dd, J = 7.4, 2.1 Hz, 1 H), 7.44–7.26 (m,
2 H), 4.40 (br., 2 H), 3.32 (m, 2 H), 3.12 (br., 1 H), 2.83 (m, 2 H)
ppm. 13C NMR (50 MHz, CDCl3): δ = 208.4, 202.0, 140.8, 133.9,
132.0, 128.9, 127.6, 118.8, 68.3, 36.2, 32.3 ppm. HRMS (CI, NH3):
calcd. for C11H15BrNO3 [M + NH4]+ 288.0211; found 288.0211.
1-Cyclopropyl-5-hydroxypentane-1,4-dione (8k): According to the
general procedure, cyanomethyl cyclopropanecarboxylate (6k;
125 mg, 1 mmol) was used; the reaction was performed in Et2O.
After work-up, flash column chromatography (silica gel; cyclohex-
ane/EtOAc, 90:10) afforded 8k (86 mg, 55%) as a colorless liquid.
5-Hydroxy-1-(naphthalen-2-yl)pentane-1,4-dione (8g): According to
the general procedure, cyanomethyl 2-naphthoate (6g; 211 mg,
1 mmol) was used; the reaction was performed in Et2O. After work-
up, flash column chromatography (silica gel; cyclohexane/EtOAc,
IR (film): ν = 3498, 1690, 1393, 1057 cm–1. 1H NMR (200 MHz,
˜
CDCl3): δ = 4.32 (s, 2 H), 2.99 (t, J = 6.2 Hz, 2 H), 2.99 (br., 1 H),
2.62 (t, J = 6.2 Hz, 2 H), 2.02–1.89 (m, 1 H), 1.06–0.97 (m, 2 H),
0.94–0.85 (m, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 208.9,
208.9, 68.2, 36.5, 31.7, 20.3, 10.8 ppm. HRMS (CI, NH3): calcd.
for C8H13O3 [M + H]+ 157.0865; found 157.0869.
70:30) afforded 8g (150 mg, 62%) as a white solid. M.p. 104 °C. IR
1
(film): ν = 3445, 1717, 1685, 1077, 822 cm–1. H NMR (200 MHz,
˜
CDCl3): δ = 8.50 (s, 1 H), 8.03–7.85 (m, 4 H), 7.65–7.51 (m, 2 H),
4.44 (d, J = 4.0 Hz, 2 H), 3.54 (t, J = 6.2 Hz, 2 H), 3.10 (t, J =
4.7 Hz, 1 H), 2.86 (t, J = 6.2 Hz, 2 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 209.0, 198.0, 135.8, 133.7, 132.6, 130.0, 129.7, 128.7,
128.7, 127.9, 127.0, 123.7, 68.5, 32.6, 32.2 ppm. HRMS (CI, NH3):
calcd. for C15H15O3 [M + H]+ 243.1021; found 243.1026.
N-[1-(Hydroxymethyl)cyclopropyl]pivalamide (7l): According to the
general procedure, cyanomethyl pivaloate (6l; 141 mg, 1 mmol) was
used; the reaction was performed in THF. After work-up, flash
column chromatography (silica gel; cyclohexane/EtOAc, 50:50 then
0:100) afforded 7l (103 mg, 60%) as a pale-yellow solid. M.p.
N-[1-(Hydroxymethyl)cyclopropyl]-1-naphthamide (7h): According
to the general procedure, cyanomethyl 1-naphthoate (6h; 211 mg,
1 mmol) was used; the reaction was performed in THF. After work-
up, flash column chromatography (silica gel; EtOAc) afforded 8h
(77 mg, 32%), followed by 7h (96 mg, 40%) as a white solid. M.p.
107 °C. IR (film): ν = 3394, 3305, 3006, 2973, 2931, 2878, 1666,
˜
1531, 1393, 1368, 1248, 1161, 1051 cm–1. 1H NMR (200 MHz,
CDCl3): δ = 6.37 (br., 1 H), 4.20 (br., 1 H), 3.58 (d, J = 20.0 Hz,
1 H), 3.48 (d, J = 20.0 Hz, 1 H), 1.12 (s, 9 H), 0.91–0.80 (m, 2 H),
0.79–0.68 (m, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 191.9,
69.7, 38.6, 35.4, 27.5, 13.0 ppm. HRMS (CI, NH3): calcd. for
C14H25N2O4 [2 ϫ (M – tBu) + H]+ 285.1814; found 285.1821.
149 °C. IR (film): ν = 3274, 1639, 1514, 1301, 1051, 778, 763 cm–1.
˜
1H NMR (200 MHz, CDCl3): δ = 8.32–8.09 (m, 1 H), 7.98–7.67
(m, 2 H), 7.61–7.39 (m, 3 H), 7.32 (dd, J = 8.0, 7.2 Hz, 1 H), 6.89
(s, 1 H), 4.30 (s, 1 H), 3.62 (s, 2 H), 0.91 (s, 4 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 172.5, 133.6, 133.5, 131.0, 130.0, 128.4,
127.3, 126.5, 125.2, 125.1, 124.6, 69.5, 36.0, 12.9 ppm. HRMS
(ESI): calcd. for C15H16NO2 [M + H] 242.1176; found 242.1172.
1-Hydroxy-6,6-dimethylheptane-2,5-dione (8l): According to the ge-
neral procedure, cyanomethyl pivaloate (6l; 141 mg, 1 mmol) was
used; the reaction was performed in Et2O. After work-up, flash
5-Hydroxy-1-(naphthalen-1-yl)pentane-1,4-dione (8h): According to column chromatography (silica gel; cyclohexane/EtOAc, 70:30) af-
the general procedure, cyanomethyl 1-naphthoate (6h; 211 mg,
1 mmol) was used; the reaction was performed in Et2O. After work-
up, flash column chromatography (silica gel; cyclohexane/EtOAc,
70:30) afforded 8h (159 mg, 66%) as an orange solid. M.p. 77 °C.
forded 8l (96 mg, 56%) as a colorless liquid. IR (film): ν = 3482,
˜
1
1699, 1365, 1054 cm–1. H NMR (200 MHz, CDCl3): δ = 4.28 (s,
2 H), 3.13 (br., 1 H), 2.86 (t, J = 6.1 Hz, 2 H), 2.55 (t, J = 6.1 Hz,
2 H), 1.11 (s, 9 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 214.4,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O31251
/KAP1
Date: 28-10-13 17:45:21
Pages: 11
P. Setzer, G. Forcher, F. Boeda, M. S. M. Pearson-Long, P. Bertus
FULL PAPER
209.0, 68.3, 43.9, 31.9, 30.7, 26.6 ppm. HRMS (CI, NH3): calcd.
for C9H17O3 [M + H]+ 173.1178; found 173.1184.
128.4, 125.6, 68.3, 34.2, 31.9 ppm. HRMS (CI, NH3): calcd. for
C13H15O3 [M + H]+ 219.1021; found 219.1021.
N-[1-(Hydroxymethyl)cyclopropyl]-1-adamantanecarbamide (7m): 1-Hydroxy-7-phenylhept-6-yne-2,5-dione (8q): According to the ge-
According to the general procedure, cyanomethyl 1-adamantane-
carboxylate (6m; 219 mg, 1 mmol) was used; the reaction was per-
formed in THF. After work-up, flash column chromatography (sil-
ica gel; EtOAc) afforded 7m (172 mg, 69%) as a white solid. M.p.
neral procedure, cyanomethyl 3-phenylpropynoate (6q; 185 mg,
1 mmol) was used; the reaction performed in Et2O. After work-
up, flash column chromatography (silica gel; cyclohexane/EtOAc,
70:30) afforded 8q (91 mg, 42%) as a brown oil. IR (film): ν =
˜
139 °C. IR (film): ν = 3334, 3280, 2902, 2851, 1626, 1518, 1447,
3393, 3304, 3005, 2972, 2929, 2879, 2198, 1718, 1666, 1532, 1399,
˜
1302, 1279, 1048, 887, 688 cm–1. 1H NMR (200 MHz, CDCl3): δ = 1368, 1162, 1052 cm–1. 1H NMR (200 MHz, CDCl3): δ = 7.62–7.52
6.09 (br., 1 H), 4.43 (br., 1 H), 3.58 (s, 2 H), 2.06–1.95 (m, 3 H), (m, 2 H), 7.47–7.31 (m, 3 H), 4.40 (d, J = 20.0 Hz, 1 H), 4.30 (d,
1.84–1.78 (m, 6 H), 1.76–1.60 (m, 6 H), 0.97–0.72 (m, 4 H) ppm.
J = 20.0 Hz, 1 H), 3.10 (t, J = 6.3 Hz, 2 H), 3.04 (br., 1 H), 2.75
13C NMR (50 MHz, CDCl3): δ = 181.4, 70.0, 40.5, 39.3, 39.2, 36.5,
(t, J = 6.3 Hz, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 207.9,
36.4, 35.4, 28.1, 28.0, 13.1 ppm. HRMS (CI, NH3): calcd. for 185.3, 133.2, 131.0, 128.8, 119.8, 91.9, 87.4, 68.3, 38.9, 31.8 ppm.
C15H24NO2 [M + H]+ 250.1807; found 250.1807.
HRMS (CI, NH3): calcd. for C13H13O3 [M + H]+ 217.0865; found
217.0881.
1-(Adamantan-1-yl)-5-hydroxypentane-1,4-dione (8m): According to
the general procedure, cyanomethyl 1-adamantanecarboxylate (6m;
219 mg, 1 mmol) was used; the reaction was performed in Et2O.
After work-up, flash column chromatography (silica gel; cyclohex-
ane/EtOAc, 80:20) afforded 8m (145 mg, 58%) as a pale-yellow so-
1-(Furan-2-yl)-5-hydroxypentane-1,4-dione (8r): According to the
general procedure, cyanomethyl furan-2-carboxylate (6r; 151 mg,
1 mmol) was used; the reaction was performed in Et2O. After work-
up, flash column chromatography (silica gel; cyclohexane/EtOAc,
50:50) afforded 8r (91 mg, 50%) as a white solid. M.p. 89 °C. IR
lid. M.p. 60 °C. IR (film): ν = 3531, 2914, 2901, 2887, 2852, 1711,
˜
1689, 1450, 1395, 1346, 1198, 1073, 1024 cm–1. 1H NMR
(film): ν = 3419, 1715, 1666, 1562, 1037, 771 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 4.31 (s, 2 H), 3.05 (br., 1 H), 2.85 (m, 2
(400 MHz, CDCl3): δ = 7.55 (d, J = 1.8 Hz, 1 H), 7.17 (d, J =
H), 2.57 (m, 2 H), 2.05–2.01 (m, 3 H), 1.81–1.79 (m, 6 H), 1.76– 3.6 Hz, 1 H), 6.49 (dd, J = 3.6, 1.8 Hz, 1 H), 4.32 (s, 2 H), 3.19 (t,
1.64 (m, 6 H) ppm. 13C NMR (200 MHz, CDCl3): δ = 214.1, 209.1, J = 6.4 Hz, 2 H), 3.16 (s, 1 H), 2.75 (t, J = 6.4 Hz, 2 H) ppm. 13C
68.4, 46.2, 38.4, 36.6, 31.8, 30.4, 28.0 ppm. HRMS (CI, NH3):
calcd. for C15H23O3 [M + H]+ 251.1647; found 251.1653.
NMR (100 MHz, CDCl3): δ = 208.6, 187.2, 152.2, 146.6, 117.3,
112.4, 68.2, 32.0, 31.5 ppm. HRMS (CI, NH3): calcd. for C9H11O4
[M + H]+ 183.0657; found 183.0656.
1-Hydroxypentadec-14-ene-2,5-dione (8n): According to the general
procedure, cyanomethyl undec-10-enoate (6n; 223 mg, 1 mmol) was
used; the reaction was performed in Et2O. After work-up, flash
column chromatography (silica gel; cyclohexane/EtOAc, 70:30) af-
5-Hydroxy-1-(thiophen-2-yl)pentane-1,4-dione (8s): According to
the general procedure, cyanomethyl thiophene-2-carboxylate (6s;
167 mg, 1 mmol) was used; the reaction was performed in Et2O.
After work-up, flash column chromatography (silica gel; cyclohex-
forded 8n (157 mg, 62%) as a white solid. M.p. 72 °C. IR (film): ν
˜
1
= 3338, 1702, 1643, 1027 cm–1. H NMR (400 MHz, CDCl3): δ = ane/EtOAc, 70:30) afforded 8s (129 mg, 65%) as a beige solid. M.p.
5.80 (ddt, J = 17.1, 10.3, 6.7 Hz, 1 H), 4.98 (br. d, J = 17.1 Hz, 1
112 °C. IR (film): ν = 3427, 3104, 2915, 1713, 1655, 1515, 1413,
˜
H), 4.92 (br. d, J = 10.3 Hz, 1 H), 4.32 (s, 2 H), 2.97 (br., 1 H), 1393, 1358, 1235, 1216, 1055 cm–1. 1H NMR (200 MHz, CDCl3):
2.80 (t, J = 6.2 Hz, 2 H), 2.62 (t, J = 6.2 Hz, 2 H), 2.44 (t, J =
7.4 Hz, 2 H), 2.03 (br. q, J = 7.1 Hz, 2 H), 1.60–1.54 (m, 2 H),
1.40–1.34 (m, 2 H), 1.30–1.26 (m, 8 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 209.3, 208.8, 139.2, 114.2, 68.2, 42.6, 36.0, 33.8, 31.7,
29.3, 29.3, 29.2, 29.1, 28.9, 23.8 ppm. HRMS (CI, NH3): calcd. for
C15H27O3 [M + H]+ 255.1960; found 255.1967.
δ = 7.76 (d, J = 3.7 Hz, 1 H), 7.64 (d, J = 4.8 Hz, 1 H), 7.13 (m, 1
H), 4.43 (d, J = 19.1 Hz, 1 H), 4.33 (d, J = 19.1 Hz, 1 H), 3.34 (t,
J = 6.3 Hz, 2 H), 3.08 (br., 1 H), 2.80 (t, J = 6.3 Hz, 2 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 208.7, 191.0, 143.3, 134.0, 132.3,
128.3, 68.4, 33.0, 32.0 ppm. HRMS (CI, NH3): calcd. for C9H11O3S
[M + H]+ 199.0429; found 199.0430.
(E)-1-Hydroxyoct-6-ene-2,5-dione (8o): According to the general
procedure, cyanomethyl (E)-but-2-enoate (6o; 125 mg, 1 mmol) was
used; the reaction was performed in Et2O. After work-up, flash
column chromatography (silica gel; cyclohexane/EtOAc, 50:50) af-
N-[1-(1-Hydroxyethyl)cyclopropyl]-1-benzamide (7u): According to
the general procedure, 1-cyanoethyl benzoate (6u; 175 mg, 1 mmol)
was used; the reaction was performed in THF. After work-up, flash
column chromatography (silica gel; cyclohexane/EtOAc, 80:20 to
0:100) afforded 8u (107 mg, 52%), followed by 7u (18 mg, 9%) as
forded 8o (66 mg, 42%) as a white solid. M.p. 48 °C. IR (film): ν
˜
= 3425, 1719, 1688, 1628, 981, 637 cm–1. 1H NMR (200 MHz,
a white solid. M.p. 95 °C. IR (film): ν = 3297, 2971, 2924, 1640,
˜
CDCl3): δ = 6.85 (dq, J = 15.8, 6.8 Hz, 1 H), 6.07 (dq, J = 15.8, 1519, 1486, 1309, 1098, 1027, 694 cm–1. 1H NMR (200 MHz,
1.7 Hz, 1 H), 4.27 (s, 2 H), 3.20 (br., 1 H), 2.89 (t, J = 6.3 Hz, 2 CDCl3): δ = 7.80–7.72 (m, 2 H), 7.55–7.35 (m, 3 H), 7.11 (br., 1
H), 2.61 (t, J = 6.3 Hz, 2 H), 1.85 (dd, J = 6.8, 1.7 Hz, 3 H) ppm. H), 4.97 (br., 1 H), 3.38 (q, J = 6.3 Hz, 1 H), 1.22 (d, J = 6.3 Hz,
13C NMR (50 MHz, CDCl3): δ = 208.9, 197.9, 143.6, 131.4, 68.3, 3 H), 1.18–0.74 (m, 4 H) ppm. 13C NMR (50 MHz, CDCl3): δ =
33.4, 31.8, 18.4 ppm. HRMS (CI, NH3): calcd. for C8H13O3 [M +
170.8, 133.7, 132.1, 128.7, 127.2, 74.0, 38.6, 20.0, 14.3, 12.5 ppm.
HRMS (CI, NH3): calcd. for C12H16NO2 [M + H]+ 206.1181;
found 206.1188.
H]+ 157.0865; found 157.0869.
(E)-1-Hydroxy-7-phenylhept-6-ene-2,5-dione (8p): According to the
general procedure, cyanomethyl cinnamate (6p; 187 mg, 1 mmol)
was used; the reaction was performed in Et2O. After work-up, flash
column chromatography (silica gel; cyclohexane/EtOAc, 90:10) af-
5-Hydroxy-1-phenylhexane-1,4-dione (8u): According to general the
procedure, 1-cyanoethyl benzoate (6u; 175 mg, 1 mmol) was used;
the reaction was performed in Et2O. After work-up, flash column
chromatography (silica gel; cyclohexane/EtOAc, 60:40) afforded 8u
forded 8p (98 mg, 45%) as a white solid. M.p. 74 °C. IR (film): ν
˜
1
= 3486, 1714, 1654, 1073, 690 cm–1. H NMR (200 MHz, CDCl3): (115 mg, 56%) as a white solid. M.p. 52 °C. IR (film): ν = 3446,
˜
δ = 7.59 (d, J = 16.3 Hz, 1 H), 7.57–7.50 (m, 2 H), 7.43–7.37 (m, 1713, 1682, 1014, 689 cm–1. 1H NMR (200 MHz, CDCl3): δ = 7.97–
2 H), 6.75 (d, J = 16.2 Hz, 1 H), 4.38 (s, 2 H), 3.11 (t, J = 6.3 Hz, 7.92 (m, 2 H), 7.59–7.39 (m, 3 H), 4.38 (dq, J = 7.1, 4.4 Hz, 1 H),
2 H), 3.10 (br., 1 H), 2.74 (t, J = 6.3 Hz, 2 H) ppm. 13C NMR
3.59 (d, J = 4.5 Hz, 1 H), 3.35 (t, J = 6.3 Hz, 2 H), 2.87 (q, J =
(50 MHz, CDCl3): δ = 208.9, 198.0, 143.2, 134.3, 130.7, 129.0, 6.3 Hz, 2 H), 1.45 (d, J = 7.1 Hz, 3 H) ppm. 13C NMR (50 MHz,
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Date: 28-10-13 17:45:21
Pages: 11
Ti-Mediated Addition of Grignard Reagents to Acyl Cyanohydrins
CDCl3): δ = 211.7, 198.2, 136.4, 133.4, 128.7, 128.1, 72.9, 32.5,
31.3, 19.9 ppm. HRMS (CI, NH3): calcd. for C12H15O3 [M + H]+
207.1021; found 207.1026.
39.7, 29.3, 13.1 ppm. HRMS (CI, NH3): calcd. for C12H16NO2 [M
+ H]+ 206.1181; found 206.1180.
6-Hydroxy-1-phenylhexane-1,4-dione (15a): Colorless oil. IR (film):
1
5-Hydroxy-1,5-diphenylpentane-1,4-dione (8v): According to the ge-
neral procedure, 1-cyanobenzyl benzoate (6v; 237 mg, 1 mmol) was
used; the reaction was performed in Et2O. After work-up, flash
column chromatography (silica gel; cyclohexane/EtOAc, 95:5 then
ν = 3413, 2904, 1709, 1680, 1397, 1357, 1211, 1044, 688 cm–1. H
˜
NMR (200 MHz, CDCl3): δ = 8.02–7.94 (m, 2 H), 7.63–7.40 (m, 3
H), 3.90 (t, J = 5.5 Hz, 2 H), 3.37–3.26 (m, 2 H), 2.95–2.75 (m, 5
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 209.1, 197.7, 135.5,
132.4, 127.7, 127.1, 57.2, 44.1, 35.8, 31.5 ppm. HRMS (CI, NH3):
calcd. for C12H15O3 [M + H]+ 207.1021; found 207.1015.
50:50) afforded 8v (139 mg, 52%) as a brown oil. IR (film): ν =
˜
3452, 3063, 3031, 2915, 1714, 1682, 1597, 1581, 1493, 1449, 1354,
1215, 1014 cm–1. 1H NMR (400 MHz, CDCl3): δ (40:60 mixture of
two rotamers) = 7.95–7.91 (m, 2 H), 7.58–7.53 (m, 1 H), 7.47–7.32
(m, 7 H), 5.29 (s, 1 H), 4.37 (br., 1 H), 3.41 (dd, J = 8.1, 5.6 Hz,
0.4 H), 3.36 (dd, J = 8.1, 5.6 Hz, 0.6 H), 3.17 (t, J = 5.8 Hz, 0.6
H), 3.12 (t, J = 5.8 Hz, 0.4 H), 2.93 (dd, J = 8.1, 5.4 Hz, 0.4 H),
2.88 (dd, J = 8.1, 5.4 Hz, 0.6 H), 2.59 (t, J = 5.8 Hz, 0.6 H), 2.54
(t, J = 5.8 Hz, 0.4 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
208.8, 198.1, 138.2, 136.3, 133.4, 129.1, 128.8, 128.7, 128.1, 127.6,
80.0, 32.8, 31.9 ppm. HRMS (CI, NH3): calcd. for C17H17O3 [M +
H]+ 269.1178; found 269.1183.
Reaction with 2-Cyanoethyl Butanoate (13b): According to the gene-
ral procedure, 2-cyanoethyl propanoate (13b; 127 mg, 1 mmol) was
used; the reaction was performed in Et2O. After work-up, flash
column chromatography (silica gel; CH2Cl2/iPrOH, 99:1 to 95:5)
afforded 15b (51 mg, 32%) followed by 14b (37 mg, 24%).
N-[1-(2-Hydroxyethyl)cyclopropyl]propionamide (14b): Colorless oil.
IR (film): ν = 3271, 2939, 1639, 1531, 1421, 1374, 1234, 1064, 1020,
˜
948 cm–1. 1H NMR (200 MHz, CDCl3): δ = 6.13 (br., 1 H), 4.45
(br., 1 H), 3.65–3.50 (m, 2 H), 2.11 (q, J = 7.5 Hz, 2 H), 1.62–1.53
(m, 2 H), 1.07 (t, J = 7.5 Hz, 3 H), 0.84–0.69 (m, 4 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 175.2, 58.6, 39.8, 28.7, 13.0, 9.0 ppm.
HRMS (CI, NH3): calcd. for C8H16NO3 [M + H]+ 158.1181; found
158.1181.
1-(4-Bromophenyl)-5-hydroxyhexane-1,4-dione (8w): According to
the general procedure, 1-cyanoethyl 4-bromobenzoate (6w; 254 mg,
1 mmol) was used; the reaction was performed in Et2O. After work-
up, flash column chromatography (silica gel; cyclohexane/EtOAc,
60:40) afforded 8w (284 mg, 50%) as a beige solid. M.p. 75 °C. IR
1-Hydroxyoctane-3,6-dione (15b): Colorless oil. IR (film): ν = 3408,
˜
2921, 1703, 1460, 1398, 1374, 1103, 1046, 794 cm–1. 1H NMR
(200 MHz, CDCl3): δ = 3.85–3.74 (m, 2 H), 2.72–2.60 (m, 7 H),
2.42 (q, J = 7.3 Hz, 2 H), 0.99 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 209.2, 209.1, 57.1, 43.9, 35.6, 34.8, 34.7,
6.8 ppm. HRMS (CI, NH3): calcd. for C8H15O3 [M + H]+
159.1021; found 159.1028.
(film): ν = 3206, 1717, 1679, 1581, 1411, 1396, 1318, 1255, 1205,
˜
1
1065 cm–1. H NMR (200 MHz, CDCl3): δ = 7.87–7.80 (m, 2 H),
7.57–7.64 (m, 2 H), 4.40 (qd, J = 6.8, 2.4 Hz, 1 H), 3.46 (br., 1 H),
3.33 (t, J = 6.1 Hz, 2 H), 3.03–2.74 (m, 2 H), 1.48 (d, J = 7.1 Hz,
3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 211.5, 197.2, 135.2,
132.1, 129.7, 128.7, 73.0, 32.6, 31.3, 20.0 ppm. HRMS (CI, NH3):
calcd. for C12H14BrO3 [M + H]+ 285.0126; found 285.0113.
N-[1-(2-Hydroxyethyl)cyclopropyl]pivalamide (14c): According to
the general procedure, 2-cyanoethyl pivaloate (13c; 155 mg,
1 mmol) was used; the reaction was performed in THF. After work-
up, flash column chromatography (silica gel; cyclohexane/EtOAc,
50:50 to 0:100) afforded 14c (109 mg, 59%) as a white solid. M.p.
Reaction with Cyanomethyl Diphenylcarbamate (6x): According to
the general procedure, cyanomethyl N,N-diphenylcarbamate (6x;
252 mg, 1 mmol) was used; the reaction was performed in Et2O.
After work-up, flash column chromatography (silica gel; cyclohex-
ane/EtOAc, 30:70) afforded 8x (96 mg, 34%), followed by 7x
(112 mg, 40%).
75 °C. IR (film): ν = 3262, 2959, 2869, 1636, 1519, 1455, 1206,
˜
1
1063, 894, 661 cm–1. H NMR (200 MHz, CDCl3): δ = 6.06 (br., 1
H), 4.52 (br., 1 H), 3.62 (t, J = 5.3 Hz, 2 H), 1.64 (t, J = 5.5 Hz, 2
H), 1.18 (s, 9 H), 0.79 (s, 4 H) ppm. 13C NMR (50 MHz, CDCl3):
δ = 181.0, 59.6, 41.0, 38.8, 29.6, 27.7, 14.2 ppm. HRMS (CI, NH3):
calcd. for C10H20NO2 [M + H]+ 186.1494; found 186.1497.
1,1-Diphenyl-3-[1-(hydroxymethyl)cyclopropyl]urea (7x): 1H NMR
(200 MHz, CDCl3): δ = 7.40–7.29 (m, 5 H), 7.26–7.19 (m, 5 H),
5.09 (s, 1 H), 4.31 (s, 1 H), 3.59 (s, 2 H), 0.89–0.75 (m, 4 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 158.5, 142.4, 129.5, 127.3, 126.6,
70.3, 35.8, 13.3 ppm. HRMS (CI, NH3): calcd. for C17H19N2O2 [M
+ H]+ 283.1447; found 283.1454.
Supporting Information (see footnote on the first page of this arti-
cle): Synthesis and characterization of starting nitriles 6a–x and
1
13a–c; H and 13C NMR spectra of 7 and 8.
5-Hydroxy-4-oxo-N,N-diphenylpentanamide (8x): White solid. M.p.
108.3 °C. IR (film): ν = 3356, 1713, 1640, 1590, 1487, 1452,
˜
1
1320 cm–1. H NMR (200 MHz, CDCl3): δ = 7.55–7.05 (m, 10 H),
Acknowledgments
4.31 (s, 2 H), 3.08 (br., 1 H), 2.71–2.59 (m, 4 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 209.1, 171.5, 142.5, 129.6–126.4 (m), 68.3,
33.2, 29.7 ppm. HRMS (ESI): calcd. for C17H18NO3 [M + H]+
284.1281; found 284.1279.
We gratefully acknowledge the Centre National de la Recherche
Scientifique, the Région Pays-de-la-Loire and the Ministère de
l’Enseignement Supérieur et de la Recherche for PhD fellowships.
We also thank A. Durand, P. Gangnery, F. Legros, and E. Mebold
for technical assistance and analyses.
Reaction with 2-Cyanoethyl Benzoate (13a): According to the gene-
ral procedure, 2-cyanoethyl benzoate (13a; 175 mg, 1 mmol) was
used; the reaction was performed in Et2O. After work-up, flash
column chromatography (silica gel; CH2Cl2/iPrOH, 99:1 to 98:2)
afforded 15a (49 mg, 24%), followed by 14a (102 mg, 50%).
[1] a) H. A. Reichard, G. C. Micalizio, Chem. Sci. 2011, 2, 573–
589; b) A. Wolan, Y. Six, Tetrahedron 2010, 66, 15–61; c) A.
Wolan, Y. Six, Tetrahedron 2010, 66, 3097–3133; d) O. G. Kul-
inkovich, A. de Meijere, Chem. Rev. 2000, 100, 2789–2834; e)
F. Sato, H. Urabe, S. Okamoto, Chem. Rev. 2000, 100, 2835–
2886.
N-[1-(2-Hydroxyethyl)cyclopropyl]benzamide (14a): White solid.
M.p. 93 °C. IR (film): ν = 3289, 2935, 1638, 1518, 1483, 1306, 1022,
˜
1
858, 692 cm–1. H NMR (200 MHz, CDCl3): δ = 7.80–7.70 (m, 2
[2] a) For [η5-C5Me5]2Ti(η2-ethylene), see: S. A. Cohen, P. R. Au-
burn, J. E. Bercaw, J. Am. Chem. Soc. 1983, 105, 1136–1143;
b) for [Cp2Ti(η2-C60)], see: V. V. Burlakov, A. V. Usatov, K. A.
H), 7.57–7.32 (m, 3 H), 4.61 (br., 1 H), 3.71 (dd, J = 6.1, 4.8 Hz,
2 H), 1.73 (dd, J = 6.1, 4.8 Hz, 2 H), 1.00–0.81 (m, 4 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 168.6, 133.1, 130.9, 127.7, 126.1, 58.7,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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9

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Date: 28-10-13 17:45:21
Pages: 11
P. Setzer, G. Forcher, F. Boeda, M. S. M. Pearson-Long, P. Bertus
FULL PAPER
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When the reaction was performed in THF, 4-ethyloxazol-
2(3H)-one was observed in addition to 2 and 7y (25, 18, and
10% yield, respectively).
For a competitive study of the Ti-mediated cyclopropanation
of carboxylic esters and nitriles, see: a) ref.[20a]; b) D. Gauvreau,
S. J. Dolman, G. Hughes, P. D. O’Shea, I. W. Davies, J. Org.
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The exact position of the metal atoms in dimetallated interme-
diates E, F, and G is unknown (Scheme 9). The representation
of these intermediates is purely arbitrary and used to avoid
overcrowding the scheme.
[19]
[20]
[21]
[22]
[23]
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mun. 1992, 22, 693–697.
[15] When the reaction depicted in Scheme 5 was quenched with
D2O, almost no deuterium incorporation at the methyl group
of 9a was observed by 13C NMR spectroscopic analysis.
[16] D. Seebach, E. HungerBühler, R. Naef, P. Schnurrenberger, B.
Weidmann, M. Züger, Synthesis 1982, 138–141.
[17] Stirring of a mixture of Ti(OiPr)4 and 6a in Et2O at room tem-
perature for 45 min led to 8% conversion of 6a into isopropyl
ester 10a.
[24]
O. G. Kulinkovich, Pure Appl. Chem. 2000, 72, 1715–1719.
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[27] For examples of titanium azaalkylidinene complexes (LnTi–
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[28] The titanium-mediated double addition of Grignard reagents
to nitriles involves addition to metallated imine intermediates
as a crucial step, see: a) A. B. Charette, A. Gagnon, M. Janes,
C. Mellon, Tetrahedron Lett. 1998, 39, 5147–5150; b) O. Toma-
shenko, V. Sokolov, A. Tomashevskiy, A. de Meijere, Synlett
2007, 652–654.
[29] A similar azatitanacyclopent-2-ene ring opening has recently
been postulated, see: D. Astashko, H. G. Lee, D. N. Bobrov,
J. K. Cha, J. Org. Chem. 2009, 74, 5528–5532.
[30] S. Wiedemann, D. Frank, H. Winsel, A. de Meijere, Org. Lett.
2003, 5, 753–755.
Received: August 20, 2013
Published Online: ᭿
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Job/Unit: O31251
/KAP1
Date: 28-10-13 17:45:21
Pages: 11
Ti-Mediated Addition of Grignard Reagents to Acyl Cyanohydrins
Small Ring Systems
P. Setzer, G. Forcher, F. Boeda,
M. S. M. Pearson-Long,
P. Bertus* ........................................ 1–11
Titanium-Mediated Addition of Grignard
Reagents to Acyl Cyanohydrins: Aminocy-
clopropane versus 1,4-Diketone Formation
The 1,2-dianion reactivity of the reagent
generated from EtMgBr and Ti(OiPr)4 was
illustrated when N-acyl cyanohydrins were
used as substrates (Ͼ20 examples). When
the reaction was performed in diethyl ether,
1,4-diketones were mainly isolated. Under
certain conditions, cyclopropane deriva-
tives were also obtained in good yields. A
mechanism rationalizing this dichotomy is
presented.
Keywords: Grignard reaction / Ketones /
Small ring systems / Solvent effects / Ti-
tanium
Eur. J. Org. Chem. 0000, 0–0
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