Olefin exchange-mediated cyclopropanation of nitriles with homoallylic alcohols

Article abstract of DOI:10.1016/j.tetlet.2008.04.133

We report herein olefin exchange-mediated cyclopropanation of nitriles with homoallylic alcohols. The use of homoallylic alcohols is central to the successful implementation.

Full text of DOI:10.1016/j.tetlet.2008.04.133

Tetrahedron Letters 49 (2008) 4089–4091
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Tetrahedron Letters
journal homepage: http://www.elsevier.com/locate/tetlet
Olefin exchange-mediated cyclopropanation of nitriles with
homoallylic alcohols
*
Denis N. Bobrov, Keunho Kim, Jin Kun Cha
Department of Chemistry, Wayne State University, 5101 Cass Ave, Detroit, MI 48202, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We report herein olefin exchange-mediated cyclopropanation of nitriles with homoallylic alcohols. The
use of homoallylic alcohols is central to the successful implementation.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 29 March 2008
Revised 22 April 2008
Accepted 23 April 2008
Available online 27 April 2008
Keywords:
Cyclopropanation
Aminocyclopropane
Titanium
Nitrile
Homoallylic alcohols
Since Kulinkovich and co-workers discovered an efficient cyclo-
propanation of carboxylic esters in 1989,1 the Kulinkovich reaction
has been extended to other carboxylic acid derivatives to provide
convenient access to heteroatom-substituted cyclopropanes.2 For
example, the Szymoniak group developed the preparation of
aminocyclopropanes by adaptation of the Kulinkovich reaction to
nitriles with aid of a Lewis acid.3a The successful cyclopropanation
reactions of nitriles with homologs other than the ethyl Grignard
reagent and an intramolecular version of unsaturated nitriles by
the action of the cyclohexyl Grignard reagent were also repor-
ted.3,4,5a Addition of a Lewis acid is typically required to promote
ring closure, but is unnecessary in the case of intramolecular
reactions or in the presence of a suitable chelating substituent.4
A variant involving the use of diethylzinc and lithium iodide also
appeared.5b,c In contrast, attempts to implement the olefin
exchange-mediated procedure6 to intermolecular coupling of ni-
triles and a-olefins (such as 1-hexene and 1-octene) proved to be
futile, presumably because the low-valent titanium species reacts
with the nitrile prior to olefin exchange.3d,4,7a,b We report herein
the first example of an intermolecular Kulinkovich cyclopropana-
tion between nitriles and homoallylic alcohols.
nitriles were unsuccessful under these conditions, and the high
affinity of nitriles for low-valent titanium species was presumed
to thwart the requisite olefin exchange.7a Other laboratories also
made similar observations, and competition between intra- and
intermolecular cyclopropanation reactions of x-vinyl tethered
nitriles was particularly informative.3d,4,8 Nitriles are indeed more
reactive substrates than esters and amides in the Kulinkovich reac-
tions, and the greater reactivity of nitriles has allowed chemoselec-
tive preparation of functionalized aminocyclopropanes bearing
esters and amides.3e These results prompted us to explore direct-
ing effects of homoallylic alcohols (alkoxides), because formation
of a temporary tether between a hydroxyl group and an alkoxytita-
nium species could increase the rate of olefin exchange,7b,c as well
as control diastereoselectivity.9 The synthetic utility of these sub-
strate-directed reactions has been demonstrated by us and other
laboratories.10–12
When a titanium-mediated coupling reaction of homoallylic
alcohol 1 and nitrile 2 was performed under typical olefin ex-
change reaction conditions involving slow addition of the cyclo-
hexyl Grignard reagent at 0 °C or room temperature,9,13,14
a
complex mixture of 3a and 4a was formed only in low yields, along
with the dimerization product of 110 (Scheme 1, entry 1). A modest
improvement in yields was observed when the Grignard reagent
was added at ꢀ78 °C (Scheme 1, entries 2–5). These results were
in contrast with successful coupling reactions between 1 and vinyl-
ogous esters or N-acylpyrroles under identical conditions.7b,c
A satisfactory solution was found by changing the order of addi-
tion, that is, pre-mixing of titanium isopropoxide and the cyclo-
hexyl Grignard reagent at ꢀ78 °C, followed by addition of a
Over the years, we examined low-valent titanium-mediated
cyclopropanation reactions of several carboxylic acid derivatives,
such as esters, amides, carbonates, imides, nitriles, vinylogous
esters and amides, and N-acylpyrroles, under previously developed
ligand (olefin) exchange conditions. Initial investigations on
* Corresponding author.
E-mail address: jcha@chem.wayne.edu (J. K. Cha).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.133

4090
D. N. Bobrov et al. / Tetrahedron Letters 49 (2008) 4089–4091
Me NH2
2 equiv
1
+
Lewis Acid
Ph
Ph
N
Ti(O-
i-Pr)4
MeTi(O-
-C6H11MgCl
rt
for entry 1
i-Pr)3
nitriles
0 °C to rt
3c,e,f
(3a–e)
OH
c
+
3a
+
–78 °C to rt
OH
Procedure C
5 equiv
-C6H11MgCl
1
OH
+
L.A.
O
c
N
+
Ti(O-
i-Pr)4
Me
O-
Ti
i
-Pr
4c,e,f
(H2O) (4a–e)
c-C6H11MgCl
R
N
O
4a
–78 °C to rt
for entries 2–6
Ph
N
CN
+
OH
Me
A
2
.
entry
nitrile
TMSOTf
OH
BF3 Et2O
products (%)
dimer of 1
1
2
3
4
5
6
9
3 equiv
3e (54) + 4e (0)
3e (57) + 4e (35)
3e (67) + 4e (28)
3c (65) + 4c (26)
3c (75) + 4c (11)
3f (42) + 4f (27)
3 equiv
6 equiv
3 equiv
6 equiv
6 equiv
yields (%)
solvent
entry
2
3a
8
4a
dimer
Grignard
4 equiv
4 equiv
3 equiv
3 equiv
3 equiv
4 equiv
THF
THF
Et2O
Et2O
THF
THF
1
2
3
4
5
6
1 equiv
1 equiv
1 equiv
2 equiv
2 equiv
2 equiv
20
24
24
22
14
16
21
0
7
16
19
20
11
17
0
10
0
Scheme 3. Use of Lewis acids in coupling between homoallylic alcohols and
0
nitriles.
0
forming step, since increasing amounts of Ti(O-i-Pr)4 raised relative
proportions of aminocyclopropanes (Procedure B). Noteworthy are
negligible influences on the product ratios by a heteroatom in the
nitrile substrates (9 and 10 vs 2 and 6–8), especially as the final ring
closure was documented to require addition of a Lewis acid (e.g.,
BF3ꢁEt2O) in the absence of a suitable chelating substituent.3,4
Benzonitrile is also amenable to this cyclopropanation procedure,
whereas cyclopropanation of aromatic nitriles was reported to be
less efficient than that of aliphatic counterparts.3c
Next we examined the efficacy of an external Lewis acid in max-
imizing the yield of aminocyclopropanes (Scheme 3). TMSOTf was
found to be suitable in promoting cyclopropanation in good overall
yields (Procedure C), although substantial amounts of 4 were pres-
ent even when the reactions were allowed to run longer.15,16 The
Szymoniak group demonstrated the utility of BF3ꢁEt2O for this pur-
pose. In our own studies addition of BF3ꢁEt2O prior to aqueous
workup resulted in the lower material balance due to complex
reaction mixtures (entry 1 vs entry 2 in Scheme 3).
The trans-dialkyl stereochemistry of 3b, 3c, and 3e was firmly
established by clean formation of pyrrolidines 5b, 5c, and 5e,
respectively, by standard methods (73–95%): (1) N-tosylation; (2)
the Mitsunobu reaction (Eq. 1). By analogy the remaining amino-
cyclopropanes 3a, 3d, and 3f were tentatively assigned to possess
the trans-dialkyl stereochemistry. The disappointing lack of 1,3-
diastereocontrol in the directed cyclopropanation was surprising:
3a, 3e, and 3f were obtained as ca. 1:1, 2:1, and 1.4:1 diastereo-
meric mixtures, respectively.9 Formation of 3b–d was also not
selective, but the exact ratios could not be ascertained due to the
presence of an additional stereocenter.
Scheme 1. Coupling between homoallylic alcohols and nitriles.
mixture of 1 and 2, followed by subsequent warming of the result-
ing mixture to room temperature. Additionally, use of 2 equiv of a
nitrile and 2 equiv of Ti(O-i-Pr)4 further increased overall yields
(Procedures A and B in Scheme 2).
Formation of both aminocyclopropanes and cyclic hemiacetals is
conspicuous and likely to arise from the common intermediates
(see A in Scheme 3); an excess of Ti(O-i-Pr)4 or i-PrOMgCl might
serve as a mild Lewis acid to promote the three-membered ring
NH2
1a
+
R
2 equiv of 2
(other nitriles)
Et2O
Ti(O-
+
i-Pr)4
OH
–78 °C
3a–f
+
OH
O
–78 °C to rt
c
-C6H11MgCl
R
4a–f
nitriles
a: R = BnN(Me)
6: R1 = BOM
7: R1 = Bn
8: R1 = TBDPS
b: R =
c: R =
d: R =
i
-PrCH(OBOM)
-PrCH(OBn)
-PrCH(OTBDPS)
CN
OR1
i
i
e: R = Ph
f: RCH2 = Ph
9: PhCH2CN
10: PhCN
Conditions A
1 equiv of Ti(O-
3 equiv of -C6H11MgCl
:
Conditions B
2 equiv of Ti(O-
5 equiv of -C6H11MgCl
:
1. TsCl
i
-Pr)4
i-Pr)4
H
2. PPh3
-PrO2CN=NCO2-i-Pr
c
c
NH2
i
R
ð1Þ
entry nitrile
products (%)
3a (39) 4a (31)
3b (14) 4b (46)
3c (27) 4c (34)
3d (26) 4d (37)
3e (15) 4e (24)
3f (20) 4f (19)
entry nitrile
products (%)
3a (43) 4a (40)
3b (30) 4b (50)
3c (57) 4c (35)
3d (34) 4d (33)
3e (33) 4e (30)
3f (30) 4f (38)
N
OH
Ts
1
2
3
4
5
6
2
6
7
8
2
6
R
3b,c, e
5b,c, e
7
9
7
A lack of 1,3-diastereocontrol, as well as the formation of both
cyclopropylamines and hydroxypyrans, is unsatisfactory in sharp
contrast to the 1,3-diastereoselective hydroxycyclopropanation of
homoallylic alcohols with esters.9 The 1,3-diastereoselectivity issue
can be bypassed by employing primary or achiral tertiary alcohols in
place of secondary alcohols. Interestingly, only aminocyclopropanes
were obtained from the use of tertiary homoallylic alcohols.17
8
10
11
12
8
9
9
10
10
Scheme 2. An improved method for coupling between homoallylic alcohols and
nitriles.

D. N. Bobrov et al. / Tetrahedron Letters 49 (2008) 4089–4091
4091
G.; Sorokin, V. L.; Kel’in, A. V. Zh. Org. Khim. 1993, 29, 66; (d) Kulinkovich, O. G.;
Savchenko, A. I.; Sviridov, S. V.; Vasilevskii, D. A. Mendeleev Commun. 1993, 230.
2. For reviews, see: (a) Kulinkovich, O. G. Russ. Chem. Bull., Int. Ed. 2004, 53, 1065;
(b) Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100, 2789; (c) Sato, F.;
Urabe, H.; Okamoto, S. Chem. Rev. 2000, 100, 2835.
3. (a) Bertus, P.; Szymoniak, J. Chem. Commun. 2001, 1792; (b) Bertus, P.;
Szymoniak, J. J. Org. Chem. 2002, 67, 3965; (c) Bertus, P.; Szymoniak, J. J. Org.
Chem. 2003, 68, 7133; (d) Laroche, C.; Bertus, P.; Szymoniak, J. Tetrahedron Lett.
2003, 44, 2485; (e) Bertus, P.; Szymoniak, J. Synlett 2003, 265; (f) Laroche, C.;
Harakat, D.; Bertus, P.; Szymoniak, J. Org. Biomol. Chem. 2005, 3, 3482; (g)
Laroche, C.; Behr, J.-B.; Szymoniak, J.; Bertus, P.; Plantier-Royon, R. Eur. J. Org.
Chem. 2005, 5084.
4. For a review, see: Bertus, P.; Szymoniak, J. Synlett 2007, 1346.
5. (a) Gensini, M.; Kozhushkov, S. I.; Yufit, D. S.; Howard, J. A. K.; Es-Sayed, M.; de
Meijere, A. Eur. J. Org. Chem. 2002, 2499; (b) Wiedemann, S.; Frank, D.; Winsel,
H.; de Meijere, A. Org. Lett. 2003, 5, 753; (c) de Meijere, A.; Kozhushkov, S. I.;
Savchenko, A. I. J. Organomet. Chem. 2004, 689, 2033.
6. (a) Lee, J.; Kang, C. H.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996, 118, 291; (b) Lee,
J.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996, 118, 4198.
7. (a) Lee, J.; Lee, J. C.; Cha, J. K., unpublished results.; See also: (b) Masalov, N.;
Feng, W.; Cha, J. K. Org. Lett. 2004, 6, 2365; (c) Epstein, O. L.; Seo, J. M.; Masalov,
N.; Cha, J. K. Org. Lett. 2005, 7, 2105.
8. Laroche, Cf. C.; Bertus, P.; Szymoniak, J. Chem. Commun. 2005, 3030.
9. Quan, L. G.; Kim, S.-H.; Lee, J. C.; Cha, J. K. Angew. Chem., Int. Ed. 2002, 41, 2160.
10. (a) Savchenko, A. I.; Kulinkovich, O. G. Zh. Org. Khim. 1997, 33, 913; (b) Isakov,
V. E.; Kulinkovich, O. G. Synlett 2003, 967.
11. (a) Ryan, J.; Micalizio, G. C. J. Am. Chem. Soc. 2006, 128, 2764; (b) Reichard, H. A.;
Micalizio, G. C. Angew. Chem., Int. Ed. 2007, 46, 1440; (c) Takahashi, M.;
Micalizio, G. C. J. Am. Chem. Soc. 2007, 129, 7514.
When an alcohol of 1 was protected as the corresponding TIPS
or benzyl ether, no coupling product (either 3 or 4) was found in
the reaction mixture. Thus, the presence of an effective directing
group such as a homoallylic alcohol is necessary for the successful
titanium-mediated coupling of nitriles and terminal olefins.
Although the afore-mentioned investigations were performed
with racemic substrates, coupling of two segments bearing multi-
stereocenters is also possible by employing readily available,
nonracemic homoallylic alcohols. Such an example of segment
coupling is illustrated in Eq. 2: union of 9 and 11 delivered 12
(41%) and a 1.4:1 mixture of 13a and 13b (31%).
OH
H
2 equiv Ti(O-
i
-Pr)4
O
OBn
Ph
5 equiv
Et2O
c-C6H11MgCl
BnO
12
OH
–78 °C to rt
11
+
+
NH2
NH2
Procedure B
9
Ph
Ph
ð2Þ
OH OBn
13a
12. For a review on substrate-directed reactions, see: Hoveyda, A. H.; Evans, D. A.;
Fu, G. C. Chem. Rev. 1993, 93, 1307.
13. The cyclopentyl Grignard reagent was not used in these experiments, as it was
known to react with nitriles in the presence of titanium isopropoxides to give
the respective bicyclic aminocyclopropanes (Ref. 3d).
OH OBn
13b
In summary, olefin exchange-mediated cyclopropanation of
nitriles has been developed by employing homoallylic alcohols.
Although cyclopropanation of nitriles had previously been reported
by direct adaptation of the Kulinkovich reaction, an olefin exchange-
mediated variant was elusive. Central to the successful implementa-
tion is the use of homoallylic alcohols, which has been found in a
growing number of titanium-mediated carbon–carbon bond form-
ing reactions. Optimization is currently in progress to better control
the product ratios of hydroxypyrans to aminocyclopropanes.
14. For other examples on significant differences in the reactivity between
cyclopentyl and cyclohexyl Grignard reagents, see: (a) Quan, L. G.; Cha, J. K.
Org. Lett. 2001, 3, 2745; (b) See also Ref. 7c; (c) Lecornué, F.; Ollivier, J. Chem.
Commun. 2003, 584; (d) Cadoret, F.; Retailleau, P.; Six, Y. Tetrahedron Lett. 2006,
47, 7749.
15. TMSCl was also utilized successfully, but the resulting reactions were slightly
less clean than those with TMSOTf.
16. Representative procedure C: To
a
cooled (ꢀ78 °C) solution of Ti(O-i-Pr)4
(171 mg, 0.6 mmol) in ether (1 mL) was added dropwise a 2 M solution of c-
C6H11MgCl in ether (0.75 mL, 1.5 mmol). After the resulting bright-yellow
reaction mixture had been stirred at ꢀ78 °C for 45 min,
a solution of
homoallylic alcohol 1 (35 mg, 0.3 mmol) and nitrile 9 (70 mg, 0.6 mmol) in
ether (1.2 mL) was added at once. The reaction mixture was stirred at ꢀ78 °C
for an additional 45 min, allowed to warm to room temperature, stirred at
room temperature for 5 h, and then cooled to 0 °C. TMSOTf (0.33 mL, 1.8 mmol)
was added dropwise at 0 °C. The resulting mixture was stirred at room
temperature for 5 h and quenched at 0 °C by addition of 10% NaOH (4 mL). The
aqueous layer was separated and extracted with Et2O (5 ꢂ 5 mL). The
combined organic extracts were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified by silica gel
column chromatography (hexanes–EtOAc 5:1?2:1, followed by CH2Cl2–
methanol–25% NH4OH 50:1:0?10:1:0.04) to afford hydroxypyran 4e (20 mg,
28%) and aminocyclopropane 3e (47 mg, 67%).
Acknowledgment
We thank the National Institutes of Health (GM35956) for gen-
erous financial support.
References and notes
1. (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.; Pritytskaya, T. S. Zh. Org.
Khim. 1989, 25, 2244; (b) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.;
Savchenko, A. I.; Pritytskaya, T. S. Zh. Org. Khim. 1991, 27, 294; (c) Kulinkovich, O.
17. Kim, K.; Cha, J. K., unpublished results.