Metalated nitriles: stereodivergent cation-controlled cyclizations

Article abstract of DOI:10.1016/j.tet.2008.05.110

Stereodivergent cyclizations of γ-hydroxy cyclohexanecarbonitriles are controlled simply through judicious choice of cation in the alkylmetal base. Deprotonating a series of cyclic γ-hydroxy nitriles with i-PrMgBr generates C-magnesiated nitriles that cyclize under stereoelectronic control to cis-fused hydrindanes, decalins, and bicyclo[5.4.0]undecanes. An analogous deprotonation with BuLi triggers cyclization to trans-fused hydrindanes, decalins, and bicyclo[5.4.0]undecanes consistent with a sterically controlled electrophilic attack on an equatorial nitrile anion. Using cations to control the geometry of metalated nitriles provides a versatile, stereodivergent cyclization to cis- and trans-hydrindanes, decalins, and [5.4.0]undecanes, and reveals the key geometric requirements for intramolecular S_N2 and S_N2′ displacements.

Full text of DOI:10.1016/j.tet.2008.05.110

Tetrahedron 64 (2008) 7477–7488
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Metalated nitriles: stereodivergent cation-controlled cyclizationsq
*
Fraser F. Fleming , Yunjing Wei, Wang Liu, Zhiyu Zhang
Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, PA 15282-1530, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 April 2008
Received in revised form 23 May 2008
Accepted 23 May 2008
Available online 28 May 2008
Stereodivergent cyclizations of
cious choice of cation in the alkylmetal base. Deprotonating a series of cyclic
g
-hydroxy cyclohexanecarbonitriles are controlled simply through judi-
-hydroxy nitriles with
g
i-PrMgBr generates C-magnesiated nitriles that cyclize under stereoelectronic control to cis-fused
hydrindanes, decalins, and bicyclo[5.4.0]undecanes. An analogous deprotonation with BuLi triggers cy-
clization to trans-fused hydrindanes, decalins, and bicyclo[5.4.0]undecanes consistent with a sterically
controlled electrophilic attack on an equatorial nitrile anion. Using cations to control the geometry of
metalated nitriles provides a versatile, stereodivergent cyclization to cis- and trans-hydrindanes, decalins,
and [5.4.0]undecanes, and reveals the key geometric requirements for intramolecular SN2 and SN20
displacements.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Moderating the ligand or metal environment exerts a pro-
nounced influence on the site of coordination in metalated nitriles.
Metalated nitriles are nucleophilic chameleons, readily adapting
to the local environment by adopting different structures.2 X-ray
crystallographic analyses of metalated nitriles3 show two main
structural classes: N-metalated nitriles in which the metal co-
ordinates to the nitrile nitrogen4 and C-metalated nitriles5 in which
the metal is bound to the formally anionic carbon (Fig. 1, 1 and 2,
respectively). Crystallographically derived bond lengths for N- and
C-metalated nitriles reveal only a slight weakening of the C^N
triple bond (1.15–1.20 Å), relative to the C^N bond length of
neutral nitriles (1.14 Å),6 indicative of a predominant inductive
stabilization7 of the negative electron density. Consistent with the
inductive stabilization are short C–CN bonds8 stemming from an
electrostatic contraction between the formal anion and the
powerful electron-withdrawing nitrile group.9
The solid-state N- and C-palladated nitriles 1 and 210 differ rather
modestly in their structural features, essentially in the nature of the
phosphine ligand, but exhibit completely different coordination
modes to the same nitrile! 7Li NMR reveals basically the same
structural trends for metalated nitriles in solution; a preference for
N- or C-metalation that depends intimately on ligand and solvent,11
and minimal delocalization of the anion into the carbon–nitrogen
triple bond.9
Differences in the site of metal coordination relay into different
reactivity modes for N- and C-metalated nitriles. For example, re-
ductive elimination from the N-palladated nitrile 1 is 10 times faster
thanthatfortheanalogousC-palladatednitrile2.10 Insomecases, the
reactivity differences between N- and C-metalated nitriles translates
into completely different reaction trajectories as illustrated in the
stereodivergent alkylations of metalated cyclohexanecarbonitrile
(Scheme 1). Deprotonating cylohexanecarbonitrile (3) with LDA
t-Bu
Ph Ph
i-Pr
i-Pr
Pd
P
P
P
1.20 Å
1.35 Å
N-Metalated
C-Metalated
Pd
N
Fe
C
N
P
C
Li
1.16 Å
1.45 Å
N
C
CN
Li
Cu
Ph
Ph
i-Pr
i-Pr
LDA
MeCu
CN
N-Metalated 1
C-Metalated 2
Me
6
3
4
(70%)
(72%)
Figure 1. Structures of metalated nitriles.
Br
Br
CN
CN
q
See Ref. 1.
7
5
* Corresponding author.
Scheme 1. Regiodivergent alkylations of N- and C-metalated nitriles.
E-mail address: flemingf@duq.edu (F.F. Fleming).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.110

7478
F.F. Fleming et al. / Tetrahedron 64 (2008) 7477–7488
generates the planar, N-lithiated nitrile12 4, which attacks propargyl
bromide in an SN2 displacement leading to the alkyne 5.13 Adding
methylcopper prior to the alkylation effectively transforms the
N-lithiated nitrile 4 into the tetrahedral C-cuprated nitrile 6. Inter-
cepting 6 with propargyl bromide affords the allene 7 in an SN20
displacement reminiscent of cuprates.14
diastereomeric products, a challenging transformation that
potentially explains why cation-controlled alkylations are relatively
rare.15,25 Preliminary cyclizations26 demonstrated the viability of
stereodivergent decalin and bicyclo[4.3.0]undecane cyclizations
simply by using different alkylmetal bases to introduce mono- or
divalent metal cations (Scheme 4).
The structure and reactivity of metalated nitriles varies con-
siderably in different solvents.15 In general, hydrocarbon solvents
favor N-metalation,15 ethereal solvents favor N- or C-metalation
depending on the metal–ligand combination,11 and highly polar
solvents favor solvent-separated nitrile anions.16 Nitrile anions
were first implicated during pioneering deprotonations to de-
termine the configurational stability of ‘chiral carbanions’ (Scheme
2).17 Under kinetic conditions the deuteration of chiral cyclo-
propanecarbonitrile 8 proceeds with greater than 99.9% stereo-
chemical retention, implying the intermediacy of the pyramidal
anion 9.18 Subsequent quests to generate chiral nitrile anions19 have
proved challenging because of the relatively low barrier for
inversion of the pyramidal nitrile anion.20
HO
i-PrMgCl
BuLi
CN
Cl
THF
THF
17
CN
HO
HO
CN
cis 20
trans 19
Scheme 4. Cation-controlled cyclizations.
Expanding the cation-dependent cyclization strategy, particu-
larly for the synthesis of hydrindanes, provides critical insight into
the requirements for selectively generating cis- and trans-fused
bicyclic nitriles. Internal alkylations with allylic electrophiles reveal
stark reactivity differences in analogous cyclizations of five-, six-,
and seven-membered nitriles of direct relevance for SNi alkylations
in general. A detailed account of these cyclizations demonstrates
the dramatic influence of cation in controlling the metalated nitrile
geometry, provides a versatile method for accessing cis- and trans-
hydrindanes, decalins, and bicyclo[5.4.0]undecanes, and reveals the
key geometric requirements for intramolecular SN2 and SN20
displacements.
Retention
D
Na
H
Ph
Ph
Ph
Ph
MeONa
C
MeOD
C
C
N
N
N
Ph
Ph
8
9
10
Scheme 2. Retentive deuteration of a nitrile anion.
An alternative strategy for generating chiral, nitrile-stabilized
carbanions is to control the geometry of the anion through internal
2. Results and discussion
chelation.21 Cyclizations of
b-hydroxy nitriles have exploited this
strategy by forming internally chelated nitrile anions that selec-
tively cyclize to trans- and cis-decalin depending on the stereo-
chemistry of the adjacent hydroxyl-bearing carbon (Scheme 3).22
Probing the viability of a cation-dependent cyclization required
a short, efficient synthesis of a cyclic nitrile prototype. The g-hy-
droxy nitrile 17 admirably fulfilled this requirement (Scheme 5).
Rapid assembly of the carbon scaffold was achieved by sequential
addition of MeMgCl and 4-pentenylmagnesium bromide to oxoni-
trile 21.27 Key to this multiple bond-forming process is the alkyl-
magnesium alkoxide 22,28 which assists in preorganizing the
stereoelectronically controlled axial29 conjugate addition.30 Axial
addition of the pentenyl group occurs opposite the quaternary
methyl leading initially to a diaxial cyclohexanecarbonitrile that
subsequently equilibrates to the cyclic nitrile 23 in which both alkyl
substituents are relaxed into the equatorial orientation. Ozonolysis,
reduction, and chlorination31 (23/24/17) readily transforms the
terminal olefin into the pendant chlorobutyl electrophile required
for cyclization.
Simply deprotonating the
and warming, triggers a facile, completely stereoselective cycliza-
tion to the trans-decalin 13 whereas the diastereomeric -hydroxy
b-hydroxy nitrile 11 at low temperatures
b
nitrile 14 cyclizes to the cis-decalin 16 under identical conditions.
The divergent stereoselectivity is consistent with cyclization
through internal chelates simplistically viewed as pyramidal, nitrile
anions 12 and 15. Defining the geometry of these chiral carbanions
through lithium coordination to the electron-rich23
p-cloud of the
metalated nitrile24 effectively translates the stereochemistry of the
carbinol methine to the chiral nucleophile.
Li
N
C
Li
equatorial
CN
HO
CN
CN
HO
O
LiNEt2
(2 equiv)
( )3
Cl
Mg
CN
Cl
MeMgCl;
HO
C
11
12
trans 13
O
N
CN
BrMg
(84%)
O
Control
element
( )3
Cl2Mg
21
22
23
Cl
axial
O3; Me2S
(64%)
LiNEt2
C
CN
N
Cl
O
Li
(2 equiv)
Cl
CN
HO
HO
O
HO
Li
15
1. NaBH4 (62%)
2. CCl4, PPh3 (96%)
HO
CN
14
cis 16
24
17
Scheme 3. Chelation-controlled cyclizations of nitrile anions.
Scheme 5. Synthesis of nitrile cyclization prototype 17.
Tuning metalated nitriles through chelation suggested a more
daring strategy for controlling the geometry simply through
judicious choice of cation. The appeal stems from diverting one
nitrile through two stereodivergent alkylation manifolds to two
Cyclization of the hydroxy nitrile 17 exploits the hydroxyl group
as an internal directing group.32 Addition of i-PrMgCl to 17 leads to
the isopropylmagnesium alkoxide33 25 (Scheme 6) in which the

F.F. Fleming et al. / Tetrahedron 64 (2008) 7477–7488
7479
Grignard-type reagent is ideally anchored for the internal depro-
tonation en route to 26 and yet geometrically prevented from
attack on the electrophilic nitrile group.34 C-Magnesiated nitriles35
analogous to 26 exhibit a preference for retentive alkylation with
Stereodivergent cyclizations of the
g
-hydroxy nitrile 17 to cis-
and trans-decalin 20 and 19 stimulated homologous cyclizations to
seven-membered cis- and trans-bicyclo[5.4.0]undecane. Synthesis
of the requisite chloronitrile precursor 33 was achieved through the
sequenced addition of MeMgCl and chloropentylmagnesium
iodide43 to oxonitrile 21 (Scheme 8). Although direct, the modest
yield focused attention on increasing the nucleophilicity of chloro-
pentylmagnesium iodide to avoid the persistent isolation of the
alkenenitrile 34 resulting from 1,2- but not 1,4-addition. Increased
efficiency was achieved by adding dioxane, the intention being to
sequester the magnesium dihalide44 and promote formation of the
alkylmagnesium alkoxide assembly 31 required for the conjugate
addition. Even under optimal conditions with excess chloro-
pentylmagnesium iodide, 7% of the hydroxyalkene nitrile 34 was
isolated. Although the yield of 33 is modest, the strategy allows
direct access to the precursor required for the cation-controlled
cyclization.
alkyl halides through a three-centered, C–Mg
s
orbital overlap.36
*
Although the side-on orbital overlap is far from optimal, the
alternative co-linear approach of the chloromethylene carbon to
the small
s lobe of the C–Mg bond is sterically prohibited. Con-
sistent with this established trend, magnesiated nitrile 26 delivers
the cis-decalin 20 as the sole stereoisomer.37
Internal deprotonation
i-Pr
H
σ*
Cl
Cl
Cl
Mg
O
Mg
i-PrMgCl
OH
17
O
CN
CN
CN
2 h, rt
25
26
(74%)
CN
Cl
Axial
( )5
MgCl
Mg
Mg
CN
CN
Cl
CN
O
MeMgCl;
Cl MgI
Cl
MeMgCl;
C
HO
O
O
N
O
BrMg
Cl
O
( )5
THF-dioxane
C
( )4
Cl2Mg
Axial
21
31
32
N
ClMg
20
21
27
Scheme 6. cis-Selective cyclizations of magnesiated nitriles.
CN
Cl
CN
HO
HO
Direct formation of the cis-decalin 20 has previously been
achieved through the sequential addition of MeMgCl and chloro-
butylmagnesium bromide38 to oxonitrile 21 (Scheme 6).39
Mechanistic experiments performed prior to finding the electro-
phile-dependent alkylations of C-magnesiated nitriles, implied that
the intermediate dimagnesiated nitrile 27, generated immediately
following the axial conjugate addition, was particularly reactive
and cyclized to 20 faster than a chair-to-chair conformational in-
version (27/26).29 The preferential cyclization of the C-magne-
siated nitrile 26 to the cis-decalin 20, coupled with an anticipated
steric compression imposed by the two axial substituents in 27,
strongly implies that the Grignard addition–cyclization 21/20
actually proceeds from the dimagnesiated nitrile 27 through the
C-magnesiated nitrile 26 to the cis-decalin 20 (Scheme 6).
Cyclizing the hydroxy nitrile 17 to the diastereomeric trans-
decalin 19 was predicated on generating a dilithiated nitrile bearing
an equatorial anion. Extensive experimentation with alkyllithium
and lithium amide combinations eventually identified BuLi as the
optimum base for the cyclization (Scheme 7).40 Alkyllithiums are
prone to attack nitriles,41 implying an oxygen assisted deprotona-
tion42 of the lithium alkoxide 29. Exclusive cyclization to the trans-
decalin 19 requires overlap of an equatorially oriented nucleophile
34 (7%)
Scheme 8. 1,4-Additions to oxonitrile 17.
33 (24%)
Formation of the cyclization precursor 33 via the C-magne-
siated nitrile 32 (Scheme 8) presaged a surprisingly difficult
cyclization! Deprotonating 33 with i-PrMgCl at room temperature
conditions, which effectively cyclize the six-membered C-magne-
siated nitrile 26 (Scheme 6), fails to induce any cyclization. Coaxing
the cyclization of 33 to cis-bicyclo[5.4.0]undecane 37 (Scheme 9)
requires conversion of the chloride to the corresponding iodide 35
followed by deprotonation and heating of the reaction to reflux.
Essentially no cyclization of the iodide 35 occurs at room tem-
perature. The cis stereochemistry of 3745 is consistent with a
stereoelectronically controlled SE2(ret) displacement46 via the
C-magnesiated nitrile 36.
σ*
Mg
I
Cl
CN
I
HO
O
HO
NaI
i-PrMgCl
CN
CN
(82%)
(2.1 equiv)
with the
s orbital of the C–Cl bond, consistent with forming the
*
33
35
36
internally coordinated, pyramidal nitrile anion 30.
(90%)
CN
n-BuLi, (3.0 eq), 48 h
Li
N
C
Bu
Li
Cl
CN
Cl
CN
H
Li
O
BuLi
OH
17
O
Li
(3 equiv)
16 h, rt
HO
O
O
29
(78%)
Cl
38
trans 39
cis 37
Li
Pyramidal
anion
Scheme 9. Stereodivergent cyclizations to bicyclo[5.4.0]undecanes.
N
C
Li
O
CN
HO
(64%)
The stereodivergent cyclization of 33 with BuLi proved similarly
challenging. Following BuLi-induced deprotonation, the lithiated
nitrile 38 cyclized particularly slowly over 2 days at room tem-
perature. The extended reaction time allows for the first-formed
Cl
19
30
Scheme 7. trans-Selective cyclization with a dilithiated nitrile anion.

7480
F.F. Fleming et al. / Tetrahedron 64 (2008) 7477–7488
alkoxide to internally attack the proximal axial nitrile47 leading to
the trans-lactone 39 after an aqueous workup.48
the cyclization of ester nitrile 50 (Scheme 12). Facile access to the
ester nitrile 50 was achieved by sequential oxidation of the alde-
hyde 24 (Scheme 5) and methylation of the resulting acid 49. Ad-
dition of i-PrMgCl to ester nitrile 50 at ꢀ78 ꢁC, conditions that avoid
Grignard addition to esters,52 resulted in a very smooth cyclization,
not to the desired decalin, but to the lactone 52 (Scheme 11).53
Presumably the intermediate magnesium alkoxide 51 reacts faster
with the pendant ester than in the internal deprotonation. Alter-
native cyclization strategies with various combinations of base, the
use of aldehyde electrophiles, or with protected alcohols were
uniformly unsuccessful.
Extending the cation-controlled cylization strategy to the syn-
thesis of hydrindanes was complicated by the increased torsional
strain present in trans-fused hydrindanes49 and by an unanticipated
proximity effect en route to the cyclization precursor. Addition of
MeMgCl and 3-butenylmagnesium bromide to oxonitrile 21 affor-
ded the hydroxy nitrile 40, which requires excision of the terminal
carbon and chlorination for conversion to 44 (Scheme 10). Ozo-
nolysis of 40 and reduction with dimethylsulfide afforded not the
anticipated lactol 43 but a low yield of the enol ether 42. Although
several mechanistic sequences can lead to 42, the complete absence
of an aldehyde or lactol suggests that the axial alcohol intercepts
the intermediate carbonyl oxide to afford hydroperoxide 41 that
promptly suffers elimination. Osmium tetroxide–sodium periodate
cleavage of 40 circumvents enol ether formation, affording the very
sensitive lactol 43. Immediate reduction of the crude lactol affords
an intermediate alcohol that was successfully chlorinated without
interference of the tertiary alcohol.50
O
O
O
Me
HO
HO
O
HO
HO
Cr2O7,
K2CO3,
CN
CN
CN
MeI
H2SO4
(94%)
(78%)
24
49
50
i-PrMgCl
HO
O
O
O
i-Pr
Me
CN
O
Mg
O
HO
MeMgCl;
(64%)
O3
O
O
CN
CN
CN
CN
O
(16%)
(83%)
41
21
40
52
51
OsO4,
NaIO4
Scheme 12. Intramolecular lactonization with an ester nitrile.
BrMg
Me2S
Cyclizations of allylic chlorides provided an appealing strategy
for introducing modest yet versatile functionality into the cation-
controlled cyclization. Augmenting the synthetic attraction of the
anticipated exo-methylene products was the added opportunity to
investigate the inherent geometric requirements for intramolecular
SN2 and SN20 displacements. In practice, the strategy proved par-
ticularly rewarding because of the increased electrophilicity of the
allylic chlorides and the rapid access to the cyclization precursors
(Scheme 13). Sequential 1,2–1,4-Grignard addition to oxonitrile 21
installed the entire carbon skeleton with direct chlorination pro-
viding the chloronitriles 53a and 53b without the need for pro-
tecting the tertiary hydroxyl group. Facile cyclization occurs upon
addition of i-PrMgCl at room temperature, affording the cis-decalin
54a54 from 53a and the cis-bicyclo[5.4.0]undecane 54b from 53b
(Scheme 13).
OH
Cl
1. NaBH4
(49%)
O
HO
O
CN
CN
CN
2. Ph3P,
NCS
(75%)
44
43
42
Scheme 10. Synthesis of the hydrindane cyclization precursor 44.
Cyclizing hydroxy nitrile 44 to the cis-hydrindane 46 proceeded
smoothly upon addition of i-PrMgCl (Scheme 11). In contrast, all
attempts to coax the stereodivergent cyclization of 44 to the more
highly strained trans-hydrindane49 were frustrated by preferential
cyclization to the cis-hydrindane 46. For example, addition of BuLi
with or without additives generated only the cis-hydrindane 46.51
Presumably the inherent angle strain required to align the elec-
trophilic
s orbital of the C–Cl bond with the pyramidal p-com-
*
1. MeMgCl;
CN
plexed anion 47 is responsible for redirecting the cyclization to the
cis-hydrindane 46. Although tentative, cyclization might occur
through the C-lithiated nitrile 48, which is structurally analogous to
internally chelated organolithiums.42
IMg
( )n
HO
CN
( )n
O
2. NaOCl,
CeCl3
Cl
21
53a (n=1, 60%)
53b (n=2, 31%)
Cl
Mg Cl
HO
HO
O
i-PrMgCl
BuLi
i-PrMgCl
CN
CN
CN
(2 equiv)
(78%)
rt
-78 °C (53a)
rt (53b)
44
45
46
CN
( )n
HO
( )n
CN
HO
Li
N
(58%)
BuLi
Li
Cl
Li
Li
C
55a (n=1, 76%)
55b (n=2, 72%)
54a (n=1, 57%)
54b (n=2, 72%)
O
O
CN
Cl
47
48
Scheme 13. Stereodivergent decalin and bicyclo[5.4.0]undecane syntheses.
Scheme 11. Cyclizations to cis-hydrindane 46.
Standard addition of BuLi to 53a and 53b triggers two facile
trans-selective cyclizations. A measure of the increased reactivity is
gleaned from the comparative cyclization of 53a to 55a, which
With the aim of extending the cation-controlled cyclization
strategy to functionalized bicyclic nitriles, attention was focused on

F.F. Fleming et al. / Tetrahedron 64 (2008) 7477–7488
7481
occurred at ꢀ78 ꢁC (Scheme 13) whereas the des-methylene analog
Cl
H
R
17 (Scheme 7) required 16 h at room temperature. While optimiz-
ing the BuLi-induced cyclization of 53a, a considerable amount of
an unstable species was observed in the crude reaction mixture,
which was tentatively identified as an iminolactone resulting from
internal attack of the lithium alkoxide onto the nitrile. An expedient
solution was to add TsOH$H2O that effectively regenerates the ni-
trile without any trace of the lactone or iminolactone.55 The in-
creased reactivity of the allylic chloride-containing nitrile 53b
similarly facilitates closure of the seven-membered ring without
any lactonization (cf. 33/39, Scheme 9).56
H
Cl
Mg
Mg
Cl
HO
O
O
i-PrMgCl
CN
CN
C
N
63
64b
64a
i-PrMgCl
(37%)
S
Cl
Mg
O
HO
HO
The dramatically facilitated allylic chloride displacements
stimulated a revised approach to trans-hydrindanes. The strategy
was predicated on an allylic electrophile having a larger anti-
bonding orbital capable of overlapping an equatorially oriented
nitrile anion with a reduced torsional strain (62, Scheme 14).57
Exploring this stereoelectronic control strategy was achieved with
nitrile 57, obtained from sequential 1,2–1,4-additions to oxonitrile
21 followed by regioselective allylic oxidation and chlorination of
the intermediate nitrile 56 (Scheme 14). Cyclizing 57 with i-PrMgCl
efficiently generates the two cis-hydrindanes 59 and 6058 but with
minimal stereocontrol over the two contiguous tertiary–quater-
nary stereocenters. Presumably there is only a minimal preference
for cyclization via conformer 58b, which avoids projecting the al-
lylic methyl toward the nitrile group as in 58a, but ultimately leads
to a considerable steric interaction caused by the endo orientation
of the isopropenyl group. Cyclizing the hydroxy nitrile 57 with BuLi
provided the same two cis-hydrindanes 59 and 60. By analogy to
the related BuLi cyclization of 44 (Scheme 11) the cyclization is
tentatively presumed to proceed from the C-lithiated nitrile 61a to
60 and from 61b to 59 (Scheme 14).
H
CN
CN
CN
(34%)
59
65
60
Scheme 15. Cyclizations of allylic chlorides to cis-hydrindanes.
Exposing hydroxy nitrile 63 to BuLi did indeed provide a trans-
hydrindane although accompanied by the cis-hydrindane 59
(Scheme 16). Fortunately, the configuration of the two stereo-
centers in the trans-hydrindane 68 was unambiguously secured
through X-ray crystallographic analysis of the p-nitrobenzoate de-
rivative 66 (Fig. 2).
N
C
Li
O
CN
Cl
HO
HO
R
BuLi
CN
Cl
(34%)
63
67
trans 68
BuLi
Preferential cyclization of the dilithiated nitrile 61 to the cis-
hydrindanes 59 and 60 implies that SN20 displacement on an allylic
chloride provides insufficient orbital overlap to direct the cycliza-
tion to a trans-hydrindane. SN2 displacement of the secondary al-
lylic chloride 63 (Scheme 15), obtained by NaOCl oxidation of 56
(75%), presented an attractive solution. Although counter-intuitive,
the chirality of the allylic chloride should be relayed through the
alkylation to matched and mismatched transition structures be-
cause the C-magnesiated and dilithiated nitriles are chiral at car-
bon. Cyclizing 63 with i-PrMgCl generated the cis-fused
hydrindanes 59 and 60 in approximately equal ratios. The stereo-
chemical outcome is consistent with an SE2(ret) cyclization60 of the
R-allylic chloride through conformer 64b to the cis-hydrindane 59
and cyclization of the S-allylic chloride diastereomer to 60 via
conformation 65. Despite an effective orbital alignment for SN20
displacement, through 64a, none of the seven-membered ring was
detected in the crude reaction mixture.
S
Cl
Li
LiO
HO
H
(54%)
CN
CN
69
59
Scheme 16. Nitrile cyclizations to cis- and trans-hydrindanes.
The stereochemistry of the crystalline trans-hydrindane 66 re-
quires an SN2 displacement by an equatorial anion on the R-allylic
chloride 67 (Scheme 16). Overlap between the equatorially ori-
ented pyramidal nitrile anion 67 and the
*
s of the C–Cl bond
minimizes steric compression by staggering the isopropenyl group
between the cyclohexane ring carbons. In addition, the geometry
permits alignment of the C–Cl bond with the adjacent olefinic
p
p
-system for a stereoelectronically assisted displacement.61 The
-assistance must be integral for the cyclization because the
analogous des-chloropropyl electrophile cyclizes exclusively to a
Cl
i-PrMgCl
Cl
1. SeO2,
Cl
t-BuOOH
Mg
Mg
CN
HO
HO
O
O
(56%)
1. MeMgCl;
MgBr
CN
CN
CN
CN
58b
2. Ph3P, NCS
(77%)
rt, 1.5 h
O
21
56
57
BuLi
Cl
58a
64%
Li
N
C
Cl
Li
O
Li
Li
Li
Li
Cl
O
O
HO
HO
CN
59
CN
C
C
N
N
60
62
61a
61b
(22%)
(37%)
(48%)
(23%)
i-PrMgCl
BuLi
Scheme 14. Metalated nitrile cyclizations to cis-hydrindanes.

7482
F.F. Fleming et al. / Tetrahedron 64 (2008) 7477–7488
4. Experimental section
4.1. General methods
NMR spectra were recorded in CDCl3 (300 or 400 MHz for 1H
NMR and 75 or 100 MHz for 13C NMR) and are reported in parts per
million (d) relative to TMS using CHCl3 as an internal reference. All
reactions were performed under a nitrogen atmosphere in glass-
ware dried under high vacuum. Anhydrous solvents were distilled
from sodium benzophenone ketyl or CaH2. Bulk solvents for chro-
matography and workup of reactions were distilled through glass.
Radial chromatography was performed on a ChromatotronÒ using
individually prepared 1-, 2-, or 4-mm rotors.
4.2. General deprotonation–cyclization procedure
with i-PrMgCl
A THF solution (3 equiv) of i-PrMgCl was added dropwise to
a room temperature THF solution of g-hydroxy nitrile. After 1.5 h,
Figure 2. ORTEP of the trans-hydrindane 66.
saturated, aqueous, NH4Cl was added, the aqueous phase was
extracted with EtOAc, and the combined organic extracts were
washed with brine, dried (Na2SO4), and concentrated. Purification
by radial chromatography afforded pure material for further
characterization.
cis-hydrindane (cf. 44/46, Scheme 11). Presumably the
s –p
*
interaction sufficiently increases the cone of accessibility62 for a
facile SN2 displacement by the equatorial nitrile anion 67. Cyclizing
the S-diastereomer through an analogous conformation would
thrust the isopropenyl group into the nitrile group, which poten-
tially explains the preference for cyclization through 69 to the
cis-hydrindane 59 (Scheme 16). Despite extensive effort, the
diastereomeric chlorides were inseparable precluding their in-
dividual cyclization to test whether each selectively processes to
a cis- or trans-hydrindane.
4.3. General deprotonation–cyclization procedure with BuLi
A hexanes solution (2.1–3.0 equiv) of BuLi was added, dropwise,
to a ꢀ78 ꢁC THF solution of
g-hydroxy nitrile. After 2 h, the mixture
was allowed to warm to room temperature and after a further 1.5 h,
an aqueous solution (3 equiv) of TsOH$H2O was added. After
15 min, brine was added and the mixture was extracted with EtOAc.
The combined organic extracts were washed with brine, dried
(Na2SO4), and concentrated to afford the crude product that was
purified by radial chromatography.
3. Conclusion
Judicious choice of cation allows the stereodivergent cycliza-
tions of
b-hydroxy cyclohexenecarbonitriles to cis- and trans-
hydrindanes, decalins, and [5.4.0] undecanes. Deprotonating
b
-
4.3.1. (1S
*
,2R
*
,3S )-3-Hydroxy-3-methyl-2-(pent-4-
*
hydroxy cyclohexenecarbonitriles with i-PrMgBr or BuLi generates
two geometrically complementary metalated nitriles; divalent
magnesium favors a C-magnesiated, whereas monovalent lithium
favors an N-coordinated nitrile anion. Internal displacements of
C-magnesiated nitriles trigger stereoelectronically controlled
electrophilic substitutions to cis-fused bicyclic nitriles. In contrast,
alkylations of dilithiated nitrile anions are controlled by internal
enyl)cyclohexanecarbonitrile (23)
A THF solution (2.7 mL) of MeMgCl (7.4 mmol) was added to
a ꢀ20 ꢁC THF solution (30 mL) of 3-oxo-cyclohex-1-enecarbonitrile
(857.8 mg, 7.09 mmol). After 2 h at ꢀ20 ꢁC, a THF solution (4 mL) of
pent-4-enylmagnesium bromide was added. [5-Bromo-1-pentene
(1.26 mL, 10.6 mmol) was slowly added to a 0 ꢁC THF (4 mL) sus-
pension of Mg (314.8 mg, 13.1 mmol), activated by addition of 1,2-
dibromoethane (0.12 mL, 1.4 mmol) and allowed to react at 0 ꢁC for
1 h.] After 24 h, NH4Cl (5 mL) was added. The mixture was extrac-
ted with EtOAc and the combined organic extracts were washed
with brine, dried (Na2SO4), and concentrated. Purification by radial
chromatography (10:90, EtOAc/hexanes) afforded 1.32 g (89%) of 50
bridging of lithium to the electron-rich nitrile
p-electrons, which
generates an equatorial nitrile anion. The equatorially oriented
nucleophilic orbital is ideally aligned for cyclization to trans-
bicyclic nitriles.
Comparative cyclizations of C-magnesiated and dilithiated ni-
triles with allylic chlorides provide key insight into the geometric
requirements for intramolecular SN2 and SN20 displacements.
Stereodivergent, cation-controlled cyclizations to cis- and trans-
decalins and [5.4.0] undecanes are more facile with allylic chlorides
than for the corresponding des-methylene analogs. Comparable
cyclizations to hydrindanes depend intimately on the hybridization
of the electrophilic carbon. C-Magnesiated nitriles cyclize to
cis-hydrindanes in SN2 and SN20 displacements whereas the cycli-
zations of dilithiated nitriles appear to be redirected in SN2
displacements with secondary allylic chlorides. In this case, the
stereochemistry of the electrophilic carbon channels the cyclization
toward the trans-hydrindane. Collectively, the cation-controlled
cyclizations to cis- and trans-hydrindanes, decalins, and [5.4.0]
undecanes demonstrate the key influence of metal coordination in
controlling nitrile anion geometry and provide insight into the
geometric requirements for intramolecular SN2 and SN20
displacements.
as an oil. IR (film) 3490.6, 3076.4, 2238.4, 1640.2 cmꢀ1
(500 MHz, CDCl3) 1.24 (s, 3H), 1.30–1.40 (m, 5H), 1.44–1.78 (m,
7H), 2.05–2.09 (m, 2H), 2.69 (td, J¼11.9, 3.6 Hz, 1H), 4.93–5.03 (m,
2H), 5.76–5.86 (m, 1H); 13C NMR (125 MHz, CDCl3)
20.1, 29.0, 29.0,
29.2, 30.4, 31.4, 34.0, 39.6, 47.7, 70.8, 114.7, 122.8, 138.3.
;
1H NMR
d
d
4.3.2. (1S
*
,2R
*
,3S )-3-Hydroxy-3-methyl-2-(4-oxobutyl)-
*
cyclohexanecarbonitrile (24)
Gaseous ozone was passed through a ꢀ78 ꢁC CH2Cl2 (20 mL)
solution of 50 (331 mg, 1.6 mmol) until the distinctive blue color of
excess ozone persisted. Ozonolysis was then terminated, the solu-
tion was allowed to warm to room temperature, and then neat
Me2S (3 mL) was added dropwise. After 16 h, the mixture was
concentrated, the resulting oil was redissolved in EtOAc, and the
organic phase was then washed with brine, dried (NaSO4), and
concentrated. The crude product was purified by radial chroma-
tography (30:70, EtOAc/hexanes) to provide 210 mg (64%) of 51 as

F.F. Fleming et al. / Tetrahedron 64 (2008) 7477–7488
7483
an oil. IR (film) 3434.4, 2237.2, 1709.9 cmꢀ1
CDCl3) 1.23 (s, 3H), 1.29–1.91 (m, 11H), 1.99–2.05 (m, 1H), 2.29–
2.37 (m, 1H), 2.46 (t, J¼6.6 Hz, 1H), 2.68 (br t, J¼10.3 Hz, 1H), 9.73 (s,
1H); 13C NMR (75 MHz, CDCl3)
19.9, 21.7, 28.7, 28.8, 30.2, 31.0,
39.5, 43.8, 47.5, 70.4, 122.7, 202.6; MS (EI) m/z 209 (Mþ).
;
1H NMR (300 MHz,
identical to material previously isolated.64 For 33: IR (film) 3482.2,
2236.0 cmꢀ1; 1H NMR (500 MHz, CDCl3)
1.24 (s, 3H),1.38–1.82 (m,
d
d
15H), 2.07–2.08 (m, 1H), 2.69 (td, J¼11.7, 3.4 Hz, 1H), 3.53 (t,
d
J¼6.6 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d 20.1, 27.2, 29.0, 29.0,
29.5, 30.4, 31.4, 32.2, 39.7, 45.0, 47.7, 70.8, 122.9.; HRMS (ESI) m/z
calculated for (MþNa)þ (C14H22ClNONaþ): 278.1288, found:
278.1278.
4.3.3. (1S
*
,2R
*
,3S )-3-Hydroxy-2-(4-hydroxybutyl)-3-
*
methylcyclohexanecarbonitrile (i)
Solid NaBH4 (45.4 mg, 1.2 mmol) was added to a methanolic
solution (10 mL) of aldehyde 24 (167 mg, 0.8 mmol). After 4 h, an
aqueous solution of HCl (1 M, 3 mL) was added, and after 15 min,
10 mL ether was added, the layers were separated, and the aqueous
phase was extracted with ether (3ꢂ10 mL). The combined organic
phase was washed with H2O, brine, dried (MgSO4), filtered, con-
centrated under reduced pressure, and the residue was then puri-
fied by radial chromatography (30:70, EtOAc/hexanes) to afford
4.3.8. (1S
*
,2R
*
,3S )-3-Hydroxy-2-(5-iodopentyl)-3-
*
methylcyclohexanecarbonitrile (36)
An acetone solution (10 mL) of chloro 33 (62.6 mg, 0.3 mmol)
and NaI (771.2 mg, 5.1 mmol) was refluxed for 3 days. The mixture
was allowed to cool to room temperature, washed with saturated
NaHCO3, and then extracted with ether. The combined organic
extracts were dried (Na2SO4) and concentrated, and then the crude
product was purified by radial chromatography (8:92, EtOAc/hex-
anes) to afford 70.5 mg (82%) of 36 as an oil. IR (film) 3482.0,
152 mg (90%) of i as an oil. IR (film) 3445, 2239 cmꢀ1; 1H NMR
d 1.27
(s, 3H), 1.29–1.79 (m, 13H), 2.09 (d, J¼10.8 Hz, 1H), 2.73 (td, J¼12,
2237.3 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d 1.26 (s, 3H), 1.32–1.78 (m,
3 Hz, 1H), 3.67 (t, J¼6.0 Hz, 2H); 13C NMR
d
20.0, 25.7, 28.7, 29.1,
13H), 1.86 (p, J¼7.1 Hz, 2H), 2.09–2.11 (m, 1H), 2.70 (td, J¼11.7,
30.2, 31.3, 32.6, 39.5, 47.7, 61.9, 70.5, 123.0; HRMS (ESI) calculated
3.7 Hz, 1H), 3.20 (t, J¼7.2 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d 7.0,
for (MþNaþ) C12H21NO2Naþ: 234.1464, found: 234.1456.
20.2, 28.7, 29.2, 29.5, 30.5, 30.9, 31.5, 33.1, 39.8, 47.8, 70.9, 122.9;
HRMS (ESI) m/z calculated for (MþNa)þ (C13H22INONaþ): 358.0644,
found: 358.0620.
4.3.4. (1S
*
,2R
*
,3S )-2-(4-Chlorobutyl)-3-hydroxy-3-
*
methylcyclohexanecarbonitrile (17)
Solid PPh3 (360 mg, 1.38 mmol) and CCl4 (636 mg, 4.14 mmol)
were sequentially added to a room temperature CH2Cl2 solution
(10 mL) of i (145 mg, 0.69 mmol). After stirring overnight, the sol-
vent was removed and the crude product purified by radial chro-
matography (1:4, EtOAc/hexane) to afford 150 mg (96%) of 17 as an
4.3.9. (1S
*
,4aS
*
,9aR )-1-Hydroxy-1-methyldecahydro-1H-
*
benzo[7]annulene-4a-carbonitrile (37)
A THF solution (0.2 mL) of i-PrMgCl (0.3 mmol) was added,
dropwise, toa room temperatureTHF (3 mL) solution of 36 (35.5 mg,
0.1 mmol). After refluxing for 6 h, the solution was allowed to cool
and then saturated, aqueous, NH4Cl (2 mL) was added. The aqueous
phase was extracted with EtOAc and the combined organic extracts
were dried (Na2SO4) and concentrated. The resulting crude product
was purified by radial chromatography (30:70, EtOAc/hexanes) to
afford 19.8 mg (90%) of 37 as an oil. IR (film) 3419.8, 2227.7 cmꢀ1; 1H
oil. IR (film) 3491, 2237 cmꢀ1; 1H NMR
d 1.04 (br s, 1H), 1.28 (s, 3H),
1.33–1.84 (m, 12H), 2.11 (br d, J¼11.2 Hz, 1H), 2.72 (td, J¼12, 3 Hz,
1H), 3.67 (t, J¼6.0 Hz, 2H); 13C NMR
d 20.2, 26.9, 28.9, 29.1, 30.4,
31.4, 32.8, 39.8, 44.6, 47.7, 70.8, 122.8; MS 230 (MþH); HRMS (ESI)
calculated for (MþNaþ) C12H20ClNONaþ: 252.1126, found: 252.1127.
NMR (500 MHz, CDCl3)
d
1.26–1.97 (m, 16H), 1.50 (s, 3H), 2.08–2.17
19.7, 23.0, 23.2, 29.0, 30.1, 34.7,
4.3.5. (1R ,5S
* *
,6S
*
)-5-Hydroxy-5-methylbicyclo[4.4.0]-
(m, 2H); 13C NMR (125 MHz, CDCl3)
d
decanecarbonitrile (20)
36.3, 40.1, 40.2, 51.7, 72.2, 127.0; HRMS (ESI) m/z calculated for
Employing the general deprotonation–cyclization procedure
with i-PrMgCl (0.7 M, 0.2 mL) and chloronitrile 17 (16 mg,
0.07 mmolꢀ1) afforded 10.0 mg (74%) of the nitrile 19 spectrally
identical to material previously synthesized.63
(MþNa)þ (C13H21ONaþ): 230.1521, found: 230.1509.
4.3.10. trans-8-Methyl-13-oxa-tricyclo[6.3.2.01,7]tridecan-
12-one (39)
A hexanes solution (0.1 mL) of BuLi (0.3 mmol) was added,
dropwise, to a ꢀ78 ꢁC THF solution (2 mL) of 33 (28.7 mg,
0.1 mmol). After 2 h, the mixture was allowed to warm to room
temperature and after 2 days, an aqueous, saturated, solution (2 mL)
of NH4Cl was added. The aqueous phase was extracted with EtOAc
and then the combined organic extracts were washed with brine,
dried (Na2SO4), and concentrated. The resulting crude product was
purified by radial chromatography (10:90, EtOAc/hexanes) to afford
4.3.6. (1S
*
,6S
*
,5R )-5-Hydroxy-5-methylbicyclo[4.4.0]-
*
decanecarbonitrile (27)
Employing the general deprotonation–cyclization procedure
with BuLi (0.55 mL, 1.1 mmol) and chloronitrile 17 (115 mg,
0.5 mmol) afforded 62 mg (64%) of the nitrile 19 spectrally identical
to material previously synthesized.63
4.3.7. (1S
*
,2R
*
,3S
*
)-2-(5-Chloropentyl)-3-hydroxy-3-
15.5 mg (78%) of 39 as an oil. IR (film) 1768.0 cmꢀ1
(500 MHz, CDCl3) 1.21–1.26 (m, 2H), 1.35 (s, 3H), 1.53–1.98 (m,
15H); 13C NMR (125 MHz, CDCl3)
22.7, 24.8, 25.6, 27.1, 30.8, 32.3,
;
1H NMR
methylcyclohexanecarbonitrile (33)
d
A THF solution (1.3 mL) of MeMgCl (4.0 mmol) was added to
a ꢀ20 ꢁC THF solution (8 mL) of 3-oxo-cyclohex-1-enecarbonitrile
(456.8 mg, 3.8 mmol). After 2 h at ꢀ20 ꢁC, the THF solution was
added to a 0 ꢁC THF solution (5 mL) of 5-chloropentyl-4-enylmag-
nesium bromide. [5-Chloro-1-iodopentane (1.6 mL, 11.3 mmol) was
slowly added to a 0 ꢁC THF (5 mL) suspension of Mg (380.5 mg,
15.9 mmol), activated by addition of 1,2-dibromoethane (0.1 mL,
1.5 mmol) and allowed to react at 0 ꢁC for 1 h.] Dry dioxane (1.5 mL)
was added to the mixture and the solution was then allowed to
warm to room temperature. After 24 h, saturated, aqueous, NH4Cl
(5 mL) was added, the mixture was extracted with EtOAc, and the
combined organic extracts were then washed with brine, dried
(Na2SO4), and concentrated. Purification of the resulting crude
product by radial chromatography (10:90, EtOAc/hexanes) afforded
218.6 mg (24%) of 33 as an oil and 118.4 mg (13%) of 34 spectrally
d
36.5, 38.6, 39.3, 56.1, 61.1, 87.7, 183.5; HRMS (ESI) m/z calculated for
(MþH)þ (C13H22O2þ): 209.1542, found: 209.1554.
4.3.11. (1S
*
,2R
*
,3S )-2-(But-3-enyl)-3-hydroxy-3-
*
methylcyclohexanecarbonitrile (40)
A THF solution (1.4 mL) of MeMgCl (3.7 mmol) was added to
a ꢀ20 ꢁC THF solution (15 mL) of 3-oxo-cyclohex-1-enecarbonitrile
(427.3 mg, 3.5 mmol). After 2 h at ꢀ20 ꢁC, the intermediate mag-
nesium alkoxide was added to a 0 ꢁC THF solution (4 mL) of butenyl-
magnesium bromide. [4-Bromo-1-butene (0.5 mL, 5.3 mmol) was
slowly added to a 0 ꢁC THF (4 mL) suspension of Mg (156.8 mg,
6.5 mmol), activated by addition of 1,2-dibromoethane (0.1 mL,
0.7 mmol) and allowed to react at 0 ꢁC for 1 h.] The resulting
mixture was allowed to warm to room temperature and after

7484
F.F. Fleming et al. / Tetrahedron 64 (2008) 7477–7488
24 h, an aqueous, saturated solution (1.5 mL) of NH4Cl was added.
The aqueous phase was separated and then extracted with EtOAc
and the combined organic extracts were then washed with brine,
dried (Na2SO4), and concentrated. Purification of the resulting
crude product by radial chromatography (20:80, EtOAc/hexanes)
afforded 438.3 mg (64%) of 40 as an oil. IR (film) 3493.2,
hexanes) to afford 55 mg (75%) of 44 as an oil. IR (film) 3492.0,
2238.0 cmꢀ1; 1H NMR (500 MHz, CDCl3)
1.31 (s, 3H), 1.37–1.46 (m,
d
2H), 1.50–1.71 (m, 5H), 1.85–2.03 (m, 2H), 2.11–2.22 (m, 1H), 2.75
(td, J¼11.7, 3.4 Hz, 1H), 3.54–3.62 (m, 2H); 13C NMR (125 MHz,
CDCl3) d 20.2, 27.0, 29.1, 30.5, 31.3, 32.2, 39.9, 45.2, 47.2, 70.9, 122.7;
HRMS (ESI) m/z calculated for (MþNa)þ (C11H18ClNONaþ):
2238.3 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
1.27 (s, 3H), 1.37–1.68
238.0975, found: 238.0959.
(m, 8H), 1.82–1.89 (m, 1H), 2.09–2.41 (m, 3H), 2.73 (td, J¼11.7,
3.9 Hz, 1H), 4.99–5.09 (m, 2H), 5.79–5.87 (m, 1H); 13C NMR
4.3.15. (3aS
*
,7S
*
,7aR )-7-Hydroxy-7-methyloctahydro-1H-indene-
*
(500 MHz, CDCl3) d 20.3, 28.9, 29.2, 30.5, 31.5, 33.7, 39.8, 46.8, 70.9,
3a-carbonitrile (46)
115.2, 122.8, 138.2; HRMS (ESI) m/z calculated for (MþNa)þ
A THF solution (0.1 mL) of i-PrMgCl (3.0 M, 0.2 mmol) was
added, dropwise, to a room temperature THF (1 mL) solution of 44
(11.8 mg, 0.05 mmol). After stirring overnight, saturated, aqueous,
NH4Cl (2 mL) was added. The aqueous phase was extracted with
EtOAc and the combined organic extracts were dried (Na2SO4), and
concentrated. The resulting crude product was purified by radial
chromatography (15:85, EtOAc/hexanes) to afford 9.8 mg (78%) of
(C12H19NONaþ): 216.1359, found: 216.1357.
4.3.12. (4aR
*
,5S
*
,8aS )-8a-Methyl-4a,5,6,7,8,8a-hexahydro-4H-
*
chromene-5-carbonitrile (42)
Gaseous ozone was passed through a ꢀ78 ꢁC CH2Cl2 solution
(25 mL) of 40 (397.9 mg, 2.1 mmol) until the distinctive blue color
of excess ozone persisted. Ozonolysis was then terminated, the
solution was allowed to warm to room temperature, and then neat
Me2S (4 mL) was added. After 16 h, the mixture was concentrated,
the resulting oil was redissolved in EtOAc, and then washed with
brine, dried (NaSO4), and concentrated. The crude product was then
purified by radial chromatography (8:92, EtOAc/hexanes) to pro-
vide 59.3 mg (16%) of 42 as a solid. IR (film) 3062.5, 2236.3,
46 as an oil. IR (film) 3454.2, 2232.1 cmꢀ1
CDCl3) 1.25–1.27 (m, 1H), 1.49 (s, 3H), 1.50–1.84 (m, 9H), 1.96–2.03
(m, 2H), 2.08–2.14 (m, 1H), 2.22–2.26 (m, 1H); 13C NMR (125 MHz,
CDCl3) 20.4, 20.7, 25.2, 29.4, 30.3, 35.1, 38.2, 41.2, 54.0, 71.2, 125.7.
;
1H NMR (500 MHz,
d
d
4.3.16. 4-((1R
*
,2S
*
,6S )-6-Cyano-2-hydroxy-2-methylcyclohexyl)-
*
butanoic acid (49)
1649.9 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
1.23 (s, 3H), 1.35 (td,
An aqueous solution (1.5 mL) of Jones reagent [prepared by
mixing 3 N H2SO4 (2 mL) with NaCr2O3$2H2O (2.0 g)] was added
dropwise to a 0 ꢁC acetone solution (6 mL) of 24 After 15 min,
i-PrOH was added dropwise until the solution turned green. The
mixture was extracted with EtOAc, the combined organic extracts
were washed with H2O, dried (NaSO4), and then concentrated.
Purification of the crude product by radial chromatography
(60:40:3, EtOAc/hexanes/Et3N), afforded 403.4 mg (94%) of acid
J¼11.8, 4.4 Hz, 1H), 1.56–1.75 (m, 3H), 1.85 (br d, J¼11.7 Hz, 1H),
2.11–2.14 (m, 1H), 2.20 (br d, J¼5.8 Hz, 1H), 2.38–2.46 (m, 1H), 2.58
(td, J¼11.7, 2.9 Hz, 1H), 4.62 (t, J¼5.9 Hz, 1H), 6.23–6.25 (m, 1H); 13
C
NMR (125 MHz, CDCl3) d 20.0, 22.3, 24.3, 29.5, 29.6, 37.4, 39.2, 72.9,
96.3, 122.1, 141.2; HRMS (ESI) m/z calculated for (MþNa)þ
(C11H15NONaþ): 200.1051, found: 200.1035.
4.3.13. (1S
*
,2R
*
,3S
*
)-3-Hydroxy-2-(3-hydroxypropyl)-3-
(49) as an oil. IR (film) 3453.9, 2237.2, 1710.6 cmꢀ1
(500 MHz, CDCl3) 1.29 (s, 3H), 1.32–1.94 (m, 11H), 2.10 (d,
J¼12.7 Hz, 1H), 2.38 (br s, 2H), 2.74 (td, J¼11.7, 3.6 Hz, 1H), 3.09–3.11
(m, 1H); 13C NMR (125 MHz, CDCl3)
20.2, 24.3, 28.9, 29.0, 30.4,
31.1, 39.8, 45.1, 47.6, 70.9, 122.8, 178.6.
;
1H NMR
methylcyclohexanecarbonitrile (ii)
d
A t-BuOH solution (0.2 mL) of OsO4 (0.01 mmol) was added to
a
THF, H2O solution (3.0 mL) and (2.0 mL) of 40 (20.8 mg,
d
0.1 mmol). After 15 min, an aqueous solution (1.0 mL) of NaIO4
(115.3 mg, 0.5 mmol) was added dropwise. After 3 h, aqueous,
saturated, Na2S2O3 solution (4.0 mL) was added, the aqueous phase
was extracted with ether, and the combined organic extracts were
dried (NaSO4) and concentrated, affording 18.5 mg of the crude
lactol 43. This compound was directly reduced without further
purification. The lactol 43 was dissolved in MeOH (2 mL) and then
solid NaBH4 (28.6 mg, mmol) was added portionwise. After 3 h, HCl
1.5 mL was added, the aqueous phase was extracted with ether, and
the combined organic extracts were washed with brine, dried
(NaSO4), and concentrated. Purification of the resulting crude al-
cohol by radial chromatography (EtOA/hexanes, 25:85) afforded
10.3 mg (48%, two steps) of alcohol (ii) as an oil. IR (film) 3414.3,
4.3.17. Methyl 4-((1R
methylcyclohexyl)butanoate (50)
*
,2S
*
,6S )-6-cyano-2-hydroxy-2-
*
Neat MeI (0.3 mL, 4.7 mmol) was added to a room temperature
DMF solution (10 mL) of acid (49) (70.5 mg, 0.3 mmol) and K2CO3
(216.5 mg, 1.6 mmol). After 16 h, the mixture was washed with
brine and extracted with EtOAc. The combined organic extracts
were washed with saturated NaCl, dried (NaSO4), concentrated, and
purified by radial chromatography (40:60, EtOAc/hexanes) to pro-
vide 74.9 mg (78%) of 50 as an oil. IR (film) 3504.3, 2236.8,
1736.6 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 1.27 (s, 3H), 1.33–1.98 (m,
10H), 2.06–2.10 (m, 2H), 2.35 (br t, J¼6.6 Hz, 2H), 2.72 (td, J¼11.8,
2238.1 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
1.29 (s, 3H), 1.38–1.74 (m,
3.4 Hz, 1H), 3.66 (s, 3H); 13C NMR (75 MHz, CDCl3)
30.3, 31.1, 34.1, 39.7, 47.5, 51.5, 70.7, 122.7, 173.9.
d 20.1, 24.4, 28.9,
9H), 1.85–1.92 (m, 2H), 2.10–2.12 (m, 1H), 2.75 (td, J¼11.7, 3.7 Hz,
1H), 3.69 (t, J¼5.8 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 20.2, 25.7,
29.1, 30.4, 31.4, 32.3, 39.8, 47.4, 62.7, 70.9, 123.1; HRMS (ESI) m/z
calculated for (MþNa)þ (C11H19NO2Naþ): 220.1313, found:
220.1296.
4.3.18. (5aR
*
,6S
*
,9aS )-9a-Methyl-2-oxodecahydrobenzo[b]-
*
oxepine-6-carbonitrile (52)
A THF solution (0.5 mL) of i-PrMgBr (0.6 mmol) was added
dropwise to
a
ꢀ78 ꢁC THF solution (5 mL) of 52 (37.8 mg,
4.3.14. (1S
*
,2R
*
,3S
*
)-2-(3-Chloropropyl)-3-hydroxy-3-
0.2 mmol). After 0.5 h, the solution was allowed to warm to room
temperature and after a further 2 h, aqueous saturated NH4Cl was
added. The aqueous phase was extracted with EtOAc and the
combined organic extracts were washed with brine, dried (NaSO4),
and concentrated to afford the crude product. Purification by radial
chromatography (30:70, EtOAc/hexanes) afforded 27.3 mg (83%) of
52 as a solid, whose structure was solved by X-ray crystallography.
methylcyclohexanecarbonitrile (44)
A THF solution (2.0 mL) of alcohol (ii) (60.2 mg, 0.3 mmol) was
added dropwise to a THF solution (10.0 mL) of Ph3P (383.3 mg,
1.5 mmol) and NCS (203.0 mg, 1.5 mmol). After 16 h, the solution
cleared and then the mixture was diluted with ether. Saturated,
aqueous, NaHCO3 was added and the aqueous phase was extracted
with EtOAc. The combined organic extracts were washed with
brine, dried (Na2SO4), and concentrated, and then the crude
product was purified by radial chromatography (15:85, EtOAc/
IR (film) 3498.1, 2236.8, 1713.8 cmꢀ1
1.39 (td, J¼13.7, 4.0 Hz, 1H), 1.59 (s, 3H), 1.65–1.90 (m, 7H), 1.97 (br
t, J¼12.9 Hz, 2H), 2.10–2.28 (m, 3H), 2.64 (td, J¼14.8, 2.7 Hz, 1H),
;
1H NMR (300 MHz, CDCl3)
d

F.F. Fleming et al. / Tetrahedron 64 (2008) 7477–7488
7485
2.79–2.85 (m, 2H); 13C NMR (75 MHz, CDCl3)
28.0, 30.2, 37.2, 40.9, 45.2, 80.4, 120.9, 173.9.
d
17.6, 20.0, 25.6, 27.2,
4.3.22. (1S
*
,2R
*
,3S )-2-(4-(Chloromethyl)pent-4-enyl)-3-hydroxy-
*
3-methylcyclohexanecarbonitrile (53b)
An aqueous solution (0.4 mL) of NaOCl (0.6 mmol) was added,
dropwise, to a room temperature H2O/CH2Cl2 (1:1, 6 mL) biphasic
mixture containing iv (68.1 mg, 0.3 mmol) and CeCl3$7H2O
(218.1 mg, 0.6 mmol). After 50 min, saturated, aqueous, Na2S2O3
(3 mL) was added and the aqueous phase was then extracted with
ether. The combined organic extracts were washed with brine,
dried (Na2SO4), and concentrated. Purification by radial chroma-
tography (8:96 to 20:80, EtOAc/hexanes) afforded 131.7 mg (60%) of
53b as an oil. IR (film) 3491.5, 3082.4, 2237.8, 1642.7 cmꢀ1; 1H NMR
4.3.19. (1S
*
,2R
*
,3S )-3-Hydroxy-3-methyl-2-(3-methylbut-3-
*
enyl)cyclohexanecarbonitrile (iii)
A THF solution (2.2 mL) of MeMgCl (5.4 mmol) was added to
a ꢀ20 ꢁC THF solution (15 mL) of 3-oxo-cyclohex-1-enecarbonitrile
(626.8 mg, 5.2 mmol). After 2 h at ꢀ20 ꢁC, a THF solution (5 mL) of
3-methylbut-3-enylmagnesium iodide was added. [4-Iodo-2-
methybut-1-ene (1.4 g, 7.3 mmol) was slowly added to a 0 ꢁC THF
(5 mL) suspension of Mg (273.5 mg, 11.4 mmol), activated by
addition of 1,2-dibromoethane (0.2 mL, 2.1 mmol) and allowed to
react at 0 ꢁC for 1 h.] After 24 h, aqueous, saturated, NH4Cl (5 mL)
was added. The mixture was extracted with EtOAc and the com-
bined organic extracts were washed with brine, dried (Na2SO4), and
concentrated. Purification by radial chromatography (10:90, EtOAc/
hexanes) afforded 770.4 mg (72%) of iii as an oil. IR (film) 3499.7,
(300 MHz, CDCl3)
d 1.28 (s, 3H), 1.36–1.45 (m, 3H), 1.54–1.88 (m,
7H), 2.08–2.13 (m, 1H), 2.20–2.26 (m, 2H), 2.72 (td, J¼11.7, 3.4 Hz,
1H), 4.06 (d, J¼3.9 Hz, 2H), 5.00 (s, 1H), 5.15 (s, 1H); 13C NMR
(125 MHz, CDCl3)
d 20.2, 24.1, 27.3, 29.2, 29.3, 30.5, 31.5, 33.4, 39.8,
47.8, 48.3, 70.9, 114.8, 122.9, 144.6; HRMS (ESI) m/z calculated for
(MþH)þ (C14H22NOClþ): 256.1424, found: 256.1411.
3073.3, 2238.4, 1650.2 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 1.29 (s,
3H), 1.37–1.66 (m, 6H), 1.77 (s, 3H), 1.86–1.93 (m, 1H), 2.10–2.17 (m,
4.3.23. (1S
*
,4aR
*
,8aR )-1-Hydroxy-1-methyl-6-
*
2H), 2.32–2.38 (m, 1H), 2.74 (td, J¼11.7, 3.8 Hz, 1H), 4.74 (s, 2H); 13
C
methylenedecahydronaphthalene-4a-carbonitrile (54a)
NMR (125 MHz, CDCl3)
d
20.1, 22.2, 27.8, 28.9, 30.4, 31.3, 37.7, 39.6,
A THF solution (0.3 mL) of i-PrMgCl (0.6 mmol) was added
dropwise to a room temperature THF solution (12 mL) of 53a
(51.8 mg, 0.2 mmol). After 1.5 h, saturated, aqueous, NH4Cl (5 mL)
was added, the aqueous phase was extracted with EtOAc, and the
combined organic extracts were washed with brine, dried (Na2SO4),
and concentrated. Purification by radial chromatography (60:40 to
100:0, CH2Cl2/hexanes) afforded 24.8 mg (57%) of 54a as a solid,
whose structure was unequivocally determined by X-ray diffrac-
47.2, 70.7, 110.3,122.8,145.3; HRMS (ESI) m/z calculated for (MþH)þ
(C13H22NOþ): 208.1657, found: 208.1686.
4.3.20. (1S
*
,2R
*
,3S )-3-Hydroxy-3-methyl-2-(4-methylpent-4-
*
enyl)cyclohexanecarbonitrile (iv)
A THF solution (0.5 mL) of MeMgCl (1.4 mmol) was added to
a ꢀ20 ꢁC THF solution (6.0 mL) of 3-oxo-cyclohex-1-enecarboni-
trile (21)65 (159.4 mg, 1.3 mmol). After 2 h at ꢀ20 ꢁC, the in-
termediate magnesium alkoxide was added to a 0 ꢁC THF solution
(6.0 mL) of 4-methylpent-4-enylmagnesium iodide. [5-Iodo-2-
methylpent-1-ene (414.9 mg, 2.0 mmol) was slowly added to a 0 ꢁC
THF (6.0 mL) suspension of Mg (79.0 mg, 3.3 mmol), activated by
addition of 1,2-dibromoethane (0.05 mL, 0.5 mmol) and allowed to
react at 0 ꢁC for 1 h.] The resulting mixture was allowed to warm to
room temperature and after 24 h, an aqueous, saturated solution
(1.5 mL) of NH4Cl was added. The aqueous phase was separated,
extracted with EtOAc, and the combined organic extracts were
then washed with brine, dried (Na2SO4), and concentrated.
Purification of the resulting crude product by radial chromatog-
raphy (10:90, EtOAc/hexanes) afforded 149.2 mg (51%) of iv as an
tion. IR (film) 3481.2, 2233.4, 1652.8 cmꢀ1
CDCl3) 1.53 (s, 3H), 1.55–1.88 (m, 9H), 2.03–2.09 (m, 2H), 2.37 (br
d, J¼13.2 Hz, 1H), 2.49 (p, J¼5.9 Hz, 1H), 2.78 (br d, J¼13.2 Hz, 1H),
4.76 (s, 1H), 4.84 (s, 1H); 13C NMR (125 MHz, CDCl3)
19.4, 24.1,
30.2, 32.2, 37.2, 39.6, 43.0, 46.4, 72.4, 110.9, 125.6, 143.3; HRMS (ESI)
m/z calculated for (MþNa)þ (C13H19NOþ): 228.1364, found:
228.1375.
;
1H NMR (500 MHz,
d
d
4.3.24. (1S
*
,4aR
*
,9aR )-1-Hydroxy-1-methyl-6-
*
methylenedecahydro-1H-benzo[7]annulene-4a-carbonitrile (54b)
A THF solution (0.05 mL) of i-PrMgCl (3.0 M, 0.1 mmol) was
added dropwise to a room temperature THF solution (1 mL) of 53b
(8.1 mg, 0.03 mmol). After 4 h, saturated, aqueous, NH4Cl (1 mL)
was added, the aqueous phase was extracted with EtOAc, and the
combined organic extracts were washed with brine, dried (Na2SO4),
and concentrated. Purification by radial chromatography (10:90 to
30:70, EtOAc/hexanes) afforded 5.0 mg (72%) of 54b as an oil. IR
oil. IR (film) 3490.7, 3073.8, 2236.7, 1444.1 cmꢀ1
(500 MHz, CDCl3) 1.26 (s, 3H), 1.34–1.43 (m, 3H), 1.73 (s, 3H),
1.52–1.81 (m, 8H), 2.04–2.11 (m, 3H), 2.71 (td, J¼11.7, 3.4 Hz, 1H),
4.70 (s, 1H), 4.72 (s, 1H); 13C NMR (125 MHz, CDCl3)
20.2, 22.3,
;
1H NMR
d
d
27.6, 29.1, 29.3, 30.5, 31.5, 38.1, 39.7, 47.8, 70.9, 110.2, 122.9, 145.3;
HRMS (ESI) m/z calculated for (MþH)þ (C14H24NOþ): 222.1813,
found: 222.1794.
(film) 3477.8, 3074.1, 2230.7, 1643.2 cmꢀ1
CDCl3) 1.22–1.28 (m, 2H),1.52 (s, 3H),1.40–2.00 (m, 9H), 2.08–2.23
;
1H NMR (500 MHz,
d
(m, 2H), 2.43–2.48 (m, 1H), 2.51 (d, J¼13.6 Hz, 1H), 2.61 (d,
J¼13.6 Hz, 1H), 4.97 (s, 1H), 5.03 (s, 1H); 13C NMR (125 MHz, CDCl3)
4.3.21. (1S
*
,2R
*
,3S
*
)-2-(3-(Chloromethyl)but-3-enyl)-3-hydroxy-3-
d 19.8, 22.9, 27.9, 30.0, 34.3, 36.6, 37.7, 40.6, 45.9, 51.5, 72.3, 115.0,
methylcyclohexanecarbonitrile (53a)
126.2, 143.9; HRMS (ESI) m/z calculated for (MþNa)þ (C14H21ON-
An aqueous solution (0.9 mL) of NaOCl (1.3 mmol) was added,
dropwise, to a room temperature H2O/CH2Cl2 (1:1, 7.0 mL) biphasic
mixture containing iii (146.2 mg, 0.7 mmol) and CeCl3$7H2O
(494.7 mg, 1.3 mmol). After 50 min, saturated, aqueous, Na2S2O3
(3 mL) was added and the aqueous phase was then extracted with
CH2Cl2. The combined organic extracts were washed with brine,
dried (Na2SO4), and concentrated. Purification by radial chroma-
tography (20:80, EtOAc/hexanes) afforded 141.6 mg (83%) of 53a as
Naþ): 242.1521, found: 242.1948.
4.3.25. (1S
*
,4aS
*
,8aR )-1-Hydroxy-1-methyl-6-
*
methylenedecahydro-naphthalene-4a-carbonitrile (55a)
A hexanes solution (0.1 mL) of BuLi (0.2 mmol) was added,
dropwise, to a ꢀ78 ꢁC THF solution (2 mL) of 53a (24.8 mg,
0.1 mmol). After 2 h, the mixture was allowed to warm to room
temperature and after a further 1.5 h, a THF solution (1 mL) of
TsOH$H2O (58.5 mg, 0.3 mmol) was added. After 15 min, brine
(2 mL) was added and the mixture was extracted with EtOAc. The
combined organic extracts were washed with brine, dried (Na2SO4),
and concentrated to afford the crude product that was purified by
radial chromatography (10:90, EtOAc/hexanes) to afford 15.9 mg
an oil. IR (film) 3484.5, 2237.0 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d
1.30 (s, 3H), 1.39–1.66 (m, 6H), 1.93–2.01 (m, 1H), 2.10–2.13 (m,
1H), 2.29–2.35 (m, 3H), 2.46–2.52 (m, 1H), 2.75 (td, J¼11.7, 3.6 Hz,
1H), 4.05–4.12 (m, 2H), 5.04 (s, 1H), 5.16 (s, 1H); 13C NMR (125 MHz,
CDCl3) d 20.2, 27.8, 29.2, 30.4, 31.3, 32.9, 39.9, 47.3, 48.2, 70.9, 114.9,
122.7, 144.8; HRMS (ESI) m/z calculated for (MþNa)þ
(76%) of 55a as an oil. IR (film) 3477.7, 3074.3, 2231.4, 1649.9 cmꢀ1
1H NMR (300 MHz, CDCl3)
1.23 (s, 3H), 1.23–1.33 (m, 1H), 1.37 (td,
;
(C14H23NaNOClþ): 264.1131, found: 264.1136.
d

7486
F.F. Fleming et al. / Tetrahedron 64 (2008) 7477–7488
J¼12.5, 3.7 Hz, 2H), 1.45 (td, J¼13.7, 4.3 Hz, 2H), 1.62–1.69 (m, 3H),
1.83 (br d, J¼13.6 Hz, 1H), 2.02–2.08 (m, 3H), 2.46–2.53 (m, 2H),
4.3.29. (1S
*
,2R
*
,3S )-2-((E)-5-Chloro-4-methylpent-3-enyl)-3-
*
hydroxy-3-methylcyclohexanecarbonitrile (57)
4.85 (s, 1H), 4.89 (s, 1H); 13C NMR (125 MHz, CDCl3)
d
18.9, 24.2,
A THF solution (1.0 mL) of alcohol (v) (72.4 mg, 0.3 mmol) was
added dropwise to a THF solution (2.5 mL) of Ph3P (100.2 mg,
0.4 mmol) and NCS (51.0 mg, 0.4 mmol). After approximately 1.5 h,
the solution cleared and then the mixture was diluted with ether.
Saturated, aqueous, NaHCO3 was added and the aqueous phase was
extracted with EtOAc. The combined organic extracts were washed
with brine, dried (Na2SO4), and concentrated, and then the crude
product was purified by radial chromatography (15:85, EtOAc/
hexanes) to afford 67.1 mg (86%) of 57 as an oil. IR (film) 3491.3,
29.0, 34.2, 37.5, 40.2, 41.0, 47.1, 51.4, 70.3, 111.9, 122.7, 142.6; HRMS
(ESI) m/z calculated for (MþH)þ (C13H20NOþ): 206.1500, found:
280.1490.
4.3.26. (1S
*
,4aS
*
,9aR )-1-Hydroxy-1-methyl-6-
*
methylenedecahydro-1H-benzo[7]annulene-4a-carbonitrile (55b)
A hexanes solution (0.05 mL) of BuLi (0.2 mmol) was added,
dropwise, to a ꢀ78 ꢁC THF solution (2 mL) of 53b (18.5 mg,
0.1 mmol). After 2 h, the mixture was allowed to warm to room
temperature and after a further 1.5 h, a THF solution (1 mL) of
TsOH$H2O (58.5 mg, 0.3 mmol) was added. After 15 min, brine
(2 mL) was added and the mixture was then extracted with EtOAc.
The combined organic extracts were washed with brine, dried
(Na2SO4), and concentrated to afford the crude product that was
purified by radial chromatography (8:92, EtOAc/hexanes) to afford
11.4 mg (72%) of 55b as an oil. IR (film) 3491.9, 3073.8, 2232.4,
2239.2 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d 1.25 (s, 3H), 1.31–1.67 (m,
8H), 1.76 (s, 3H), 1.80–1.85 (m, 1H), 2.07 (br d, J¼13.6 Hz, 1H), 2.13–
2.21 (m, 1H), 2.31–2.38 (m, 1H), 2.71 (td, J¼11.7, 3.4 Hz, 1H), 4.01 (s,
2H), 5.55 (t, J¼7.1 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 14.1, 20.1,
27.9, 29.0, 29.0, 30.4, 31.4, 39.7, 47.0, 52.2, 70.7, 122.8, 130.0, 132.4;
HRMS (ESI) m/z calculated for (MþH)þ (C13H20NONaþ): 264.1131,
found: 264.1136.
1641.4 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
1.24 (s, 3H), 1.20–1.68 (m,
4.3.30. (3S
yl)octahydro-1H-indene-3a-carbonitrile (59) and
(3R ,3aR ,7S ,7aR )-7-hydroxy-7-methyl-3-(prop-1-en-2-yl)-
*
,3aR
*
,7S
*
,7aR )-7-Hydroxy-7-methyl-3-(prop-1-en-2-
*
4H), 1.77–2.13 (m, 5H), 2.30 (d, J¼13.7 Hz, 1H), 2.41 (t, J¼6.8 Hz, 1H),
2.53 (d, J¼13.7 Hz, 1H), 4.96 (s, 2H); 13C NMR (125 MHz, CDCl3)
*
*
*
*
d
19.2, 25.7, 25.9, 29.4, 34.7, 38.9, 40.0, 41.8, 49.0, 54.0, 71.7, 116.0,
octahydro-1H-indene-3a-carbonitrile (60)
123.5, 143.7; HRMS (ESI) m/z calculated for (MþK)þ (C14H21NOKþ):
A THF solution (0.09 mL) of i-PrMgCl (1.6 M) was added, drop-
wise, to a room temperature THF solution (1.5 mL) of 57 (12.2 mg,
0.048 mmol). After 1.5 h, saturated, aqueous, NH4Cl (2 mL) was
added, the aqueous phase was extracted with EtOAc, and the com-
bined organic extracts were washed with brine, dried (Na2SO4), and
concentrated. Purification by radial chromatography (10:90, EtOAc/
hexanes) afforded 2.5 mg (22%) of 59 as a solid, whose structure was
unequivocally determined by X-ray diffraction and 5.6 mg (48%) of
60 as an oil. For 59 as an oil: IR (film) 3475.5, 3076.0, 2229.4,
258.1260, found: 258.1279.
4.3.27. (1S
*
,2R
*
,3S )-3-Hydroxy-3-methyl-2-(4-methylpent-3-
*
enyl)cyclohexanecarbonitrile (56)
A THF solution (0.3 mL) of MeMgCl (0.8 mmol) was added to
a ꢀ20 ꢁC THF solution (2.5 mL) of 3-oxo-cyclohex-1-enecarboni-
trile (21)65 (87.6 mg, 0.7 mmol). After 2 h at ꢀ20 ꢁC, a THF solution
(2.5 mL) of 4-methylpent-3-enylmagnesium bromide was added.
[5-Bromo-2-methyl-2-pentene (0.2 mL, 1.3 mmol) was slowly
1641.6 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d 1.38 (s, 3H), 1.57–2.09 (m,
added to
a
0 ꢁC THF (2.5 mL) suspension of Mg (46.9 mg,
14H), 2.30 (t, J¼7.7 Hz, 1H), 2.85 (t, J¼8.1 Hz, 1H), 4.88–4.88 (m, 1H),
2.0 mmol), activated by addition of 1,2-dibromoethane (0.03 mL,
0.3 mmol) and allowed to react at 0 ꢁC for 1 h.] After 24 h, satu-
rated, aqueous, NH4Cl (2 mL) was added, the mixture was extracted
with EtOAc, and the combined organic extracts were washed with
brine, dried (Na2SO4), and concentrated. Purification of the
resulting crude by radial chromatography (10:90, EtOAc/hexanes)
afforded 102.9 mg (64%) of 56 as an oil. IR (film) 3492.3,
4.98 (p, J¼1.5 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 18.7, 21.8, 24.4,
27.5, 30.0, 31.4, 36.2, 46.2, 53.2, 53.9, 70.9, 113.9, 124.5, 144.6. For 60
as a solid: IR (film) 3486.1, 3088.2, 2231.8, 1642.9 cmꢀ1
(500 MHz, CDCl3) 1.56 (s, 3H),1.58–1.89 (m,10H),1.93 (s, 3H),1.95–
1.98 (m, 1H), 2.43 (t, J¼10.0 Hz, 1H), 2.93 (t, J¼10.0 Hz, 1H), 4.90 (s,
1H), 5.01 (s, 1H); 13C NMR (125 MHz, CDCl3)
20.9, 23.3, 23.7, 24.1,
;
1H NMR
d
d
25.4, 29.1, 34.4, 43.7, 55.2, 55.5, 71.5, 113.8, 125.4, 141.7; HRMS (ESI)
m/z calculated for (MþNa)þ (C14H21NONaþ): 242.1521, found:
242.1499. Cyclization of 57 with BuLi. A hexanes solution (0.05 mL) of
BuLi (2.5 M) was added, dropwise, to a ꢀ78 ꢁC THF solution (2.5 mL)
of 57 (14.7 mg, 0.056 mmol). After 1.5 h, the mixture was allowed to
warm to room temperature and after a further 1.5 h, a THF solution
(1 mL) of TsOH$H2O (32.8 mg) was added. After 15 min, brine (2 mL)
was added and the mixture was then extracted with EtOAc. The
combined organic extracts were washed with brine, dried (Na2SO4),
and concentrated to afford the crude product that was purified by
radial chromatography (12:88 to 1:4 to 3:7, EtOAc/hexanes) to
afford 4.6 mg (37%) of 59 as an oil and 2.8 mg of 60 as a crystalline
solid. Cyclization of 63 with i-PrMgCl. A THF solution (0.15 mL) of
i-PrMgCl (0.3 mmol) was added, dropwise, to a room temperature
THF solution (2 mL) of 63 (25.4 mg, 0.1 mmol). After 1.5 h, saturated,
aqueous, NH4Cl (2 mL) was added, the aqueous phase was extracted
with EtOAc, and the combined organic extracts were washed with
brine, dried (Na2SO4), and concentrated. Purification by radial
chromatography (5:95 to 20:80, CH2Cl2/hexanes) afforded 7.4 mg
(34%) of 60 as a solid and 8 mg (37%) of 59 as an oil.
2237.6 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 1.25 (s, 3H), 1.32–1.42
(m, 4H), 1.52–1.57 (m, 3H), 1.63 (s, 3H), 1.69 (s, 3H), 1.73–1.80 (m,
2H), 2.07–2.09 (m, 2H), 2.27 (m, 1H), 2.70 (td, J¼11.7, 3.4 Hz, 1H),
5.14 (br t, J¼1.5 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 20.2, 25.6,
28.0, 29.0, 29.0, 29.7, 30.5, 31.5, 39.6, 47.1, 70.8, 122.9, 123.9, 132.3;
HRMS (ESI) m/z calculated for (MþNa)þ (C14H23NONaþ): 244.1677,
found: 244.1659.
4.3.28. (1S
*
,2R
*
,3S )-3-Hydroxy-2-((E)-5-hydroxy-4-methylpent-
*
3-enyl)-3-methylcyclohexanecarbonitrile (v)
A CH2Cl2 solution (0.5 mL) of 56 (39.4 mg, 0.2 mmol) and
t-BuOOH (0.1 mL, 0.4 mmol) was added to a 0 ꢁC CH2Cl2 solution
(0.5 mL) of SeO2 (9.9 mg, 0.1 mmol). After 3.5 h, the mixture was
diluted with ether (1.5 mL), aqueous, saturated, NaHCO3 was added,
and the aqueous phase was extracted with ethyl acetate. The
combined organic extracts were washed with brine, dried (Na2SO4),
and concentrated, and the resulting crude product was then puri-
fied by radial chromatography (40:60 to 55:45, EtOAc/hexanes) to
afford 23.6 mg (56%) of alcohol (v) as an oil. IR (film) 3425.4,
2238.1 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d 1.26 (s, 3H), 1.32–1.63 (m,
9H), 1.67 (s, 3H), 1.80–1.87 (m, 1H), 2.07 (br d, J¼10.8 Hz, 1H), 2.16
(sextet, J¼7.3 Hz, 1H), 2.26–2.34 (m, 1H), 2.69 (td, J¼11.7, 3.2 Hz,
1H), 3.97 (s, 2H), 5.44 (t, J¼7.3 Hz, 1H); 13C NMR (125 MHz, CDCl3)
4.3.31. 7a-Cyano-octahydro-4-methyl-1-(prop-1-en-2-yl)-1-1H-
inden-4-yl 4-nitrobenzoate (vi)
A hexanes solution (0.03 mL) of BuLi (0.08 mmol) was added,
dropwise, to a ꢀ78 ꢁC THF solution (0.75 mL) of 71 (17.5 mg,
0.08 mmol). After 10 min, a THF solution (0.75 mL) of PNBCl
d
13.7, 20.1, 27.6, 28.9, 29.4, 30.4, 31.6, 39.7, 47.1, 68.5, 70.7, 123.1,
125.1, 135.5.

F.F. Fleming et al. / Tetrahedron 64 (2008) 7477–7488
7487
(16.3 mg, 0.09 mmol) was added dropwise. The mixture was
NMR (500 MHz, CDCl3)
d
0.84–0.89 (m, 1H), 1.24–1.35 (m, 3H), 1.69
refluxed for 6 h, cooled to room temperature, and then saturated
aqueous NH4Cl (2 mL) was added, the aqueous phase was extracted
with EtOAc, and the combined organic extracts were washed with
brine, dried (Na2SO4), and concentrated. Purification by radial
chromatography (8:92 to 40:60, EtOAc/hexanes) afforded 14.2 mg
(70%) of vi as a solid (mp 187–188 ꢁC), whose structure was
unequivocally determined by X-ray diffraction. IR (film) 2233.1,
(s, 3H), 1.75–1.93 (m, 3H), 1.82 (s, 3H), 1.98–2.17 (m, 2H), 2.36–2.44
(m, 1H), 3.07–3.13 (m, 2H), 4.73 (s, 1H), 5.07 (s, 1H), 8.28 (d,
J¼8.8 Hz, 2H), 8.39 (d, J¼8.8 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d
19.8, 21.9, 24.7, 25.4, 26.9, 31.9, 33.8, 46.4, 53.2, 53.9, 83.1, 114.0,
123.3, 125.3, 131.3, 136.5, 145.9, 150.4, 164.0.
Acknowledgements
1713.1 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d 1.61–1.67 (m, 1H), 1.92 (s,
3H), 1.94 (s, 3H), 1.74–2.14 (m, 9H), 2.72–2.75 (m, 1H), 3.16 (t,
Financial support from the National Institutes of Health
(2R15AI051352) and equipment grants from the National Science
Foundation (NMR: 0614785, X-ray: 024872, HRMS: 0421252) are
gratefully acknowledged.
J¼9.1 Hz, 1H), 4.88 (s, 1H), 5.00 (s, 1H), 8.12 (d, J¼8.8 Hz, 2H), 8.28
(d, J¼8.8 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d 19.9, 21.9, 24.7, 25.8,
27.2, 32.2, 32.8, 46.0, 51.6, 56.8, 114.3, 123.4, 123.5, 130.5, 136.7,
145.1, 150.4, 163.3.
Supplementary data
4.3.32. (1S
*
,2R
*
,3S )-2-(3-Chloro-4-methylpent-4-enyl)-3-
*
hydroxy-3-methylcyclohexanecarbonitrile (63)
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.05.110.
An aqueous solution (0.2 mL) of NaOCl (0.3 mmol) was added,
dropwise, to a room temperature H2O/CH2Cl2 (1:1, 4.0 mL) biphasic
mixture containing 56 (40.0 mg, 0.2 mmol) and CeCl3$7H2O
(123.3 mg, 0.3 mmol). After 50 min, saturated, aqueous, Na2S2O3
(1 mL) was added and the aqueous phase was then extracted with
CH2Cl2. The combined organic extracts were washed with brine,
dried (Na2SO4), and concentrated. Purification by radial chroma-
tography (15:85, EtOAc/hexanes) afforded 61.3 mg (75%) of a 1:1
mixture of diastereomeric 63 as an oil. IR (film) 3470.2, 3081.1,
References and notes
1. Taken in part from: Wei, Y. M.S. Thesis, Duquesne University, Pittsburgh, PA,
2007.
2. Fleming, F. F.; Zhang, Z. Tetrahedron 2005, 61, 747.
3. Boche, G. Angew. Chem., Int. Ed. Engl. 1989, 28, 277.
4. (a) Tanabe, Y.; Seino, H.; Ishii, Y.; Hidai, M. J. Am. Chem. Soc. 2000, 122, 1690; (b)
Murahashi, S.-I.; Take, K.; Naota, T.; Takaya, H. Synlett 2000, 1016; (c) Triki, S.;
2238.2, 1643.3 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d 1.26 (s, 3H), 1.36–
1.95 (m, 7H), 1.81 (s, 3H), and 1.82 (s, 3H), 2.07–2.28 (m, 2H), 2.68–
2.76 (m, 1H), 4.34 (t, J¼7.2 Hz, 1H), and 4.35 (t, J¼7.2 Hz, 1H), 4.89 (s,
1H), and 4.90 (s, 1H), 5.02 (s, 1H) and 5.03 (s, 1H); 13C NMR
Pala, J. S.; Decoster, M.; Molinie, P.; Toupet, L. Angew. Chem., Int. Ed. 1999, 38,
113; (d) Hirano, M.; Takenaka, A.; Mizuho, Y.; Hiraoka, M.; Komiya, S. J. Chem.
Soc., Dalton Trans. 1999, 3209; (e) Yates, M. L.; Arif, A. M.; Manson, J. L.; Kalm,
B. A.; Burkhart, B. M.; Miller, J. S. Inorg. Chem. 1998, 37, 840; (f) Ja¨ger, L.; Tretner,
C.; Hartung, H.; Biedermann, M. Chem. Ber. 1997, 130, 1007; (g) Zhao, H.; Heintz,
R. A.; Dunbar, K. R.; Rogers, R. D. J. Am. Chem. Soc. 1996, 118, 12844; (h) Murahashi,
S.-I.; Naota, T.; Taki, H.; Mizuno, M.; Takaya, H.; Komiya, S.; Mizuho, Y.; Oyasato,
N.; Hiraoka, M.; Hirano, M.; Fukuoka, A. J. Am. Chem. Soc. 1995, 117, 12436; (i)
Hirano, M.; Ito, Y.; Hirai, M.; Fukuoka, A.; Komiya, S. Chem. Lett. 1993, 2057; (j)
Mizuho, Y.; Kasuga, N.; Komiya, S. Chem. Lett. 1991, 2127; (k) Schlodder, R.;
Ibers, J. A. Inorg. Chem. Soc. 1974, 13, 2870; (l) Ricci, J. S.; Ibers, J. A. J. Am. Chem.
Soc. 1971, 93, 2391.
´
(125 MHz, CDCl3) d 16.9, (17.1), 20.1, (20.1), 26.6, (27.2), 28.9, (29.0),
30.3, (31.3), 35.3, (36.5), 39.7, (39.9), 47.0, (47.4), 66.8, (66.9), 70.7,
(70.8), 114.4, (114.4), 122.5, (122.7), 128.1, (128.3), 143.8, (143.9);
HRMS (ESI) m/z calculated for (MþNa)þ (C14H22NOClNaþ):
278.1282, found: 278.1299.
5. (a) Naota, T.; Tannna, A.; Kamuro, S.; Murahashi, S.-I. J. Am. Chem. Soc. 2002, 124,
6842; (b) Naota, T.; Tannna, A.; Murahashi, S.-I. J. Am. Chem. Soc. 2000, 122,
2960; (c) Alburquerque, P. R.; Pinhas, A. R.; Krause Bauer, J. A. Inorg. Chim. Acta
2000, 298, 239; (d) Ruiz, J.; Rodrı´guez, V.; Lo´pez, G.; Casabo´, J.; Molins, E.;
Miravitlles, C. Organometallics 1999, 18, 1177; (e) Ragaini, F.; Porta, F.; Fumagalli,
A.; Demartin, F. Organometallics 1991, 10, 3785; (f) Porta, F.; Ragaini, F.; Cenini,
S.; Demartin, F. Organometallics 1990, 9, 929; (g) Ko, J. J.; Bockman, T. M.; Kochi,
J. K. Organometallics 1990, 9, 1833; (h) Cowan, R. L.; Trogler, W. C. J. Am. Chem.
Soc. 1989, 111, 4750; (i) Chopra, S. K.; Cunningham, D.; Kavanagh, S.; McArdle,
P.; Moran, G. J. Chem. Soc., Dalton Trans. 1987, 2927; (j) Del Pra, A.; Forsellini, E.;
Bombieri, G.; Michelin, R. A.; Ros, R. J. Chem. Soc., Dalton Trans. 1979, 1862; (k)
Lenarda, M.; Pahor, N. B.; Calligaris, M.; Graziani, M.; Randaccio, L. J. Chem. Soc.,
Chem. Commun. 1978, 279; (l) Schlodder, R.; Ibers, J. A.; Lenarda, M.; Graziani,
M. J. Am. Chem. Soc. 1974, 96, 6893; (m) Yarrow, D. J.; Ibers, J. A.; Lenarda, M.;
Graziani, M. J. Organomet. Chem. 1974, 70, 133.
6. Le Questel, J.-Y.; Berthelot, M.; Laurence, C. J. Phys. Org. Chem. 2000, 13, 347. The
bond length is the mean of CN distance obtained from 5059 nitriles in the
Cambridge Structural Database.
7. Nitriles are powerful inductive stabilizing groups with weak delocalizing
effects: (a) Richard, J. P.; Williams, G.; Gao, J. J. Am. Chem. Soc. 1999, 121, 715; (b)
Bradamante, S.; Pagani, G. A. J. Chem. Soc., Perkin Trans. 2 1986, 1035; (c) Dayal,
S. K.; Ehrenson, S.; Taft, R. W. J. Am. Chem. Soc. 1972, 94, 9113.
4.3.33. (3S
*
,3aS
*
,7S
*
,7aR )-7-Hydroxy-7-methyl-3-(prop-1-en-2-
*
yl)octahydro-1H-indene-3a-carbonitrile (68)
A hexanes solution (0.1 mL) of BuLi (0.3 mmol) was added,
dropwise, to a ꢀ78 ꢁC THF solution (2 mL) of 63 (25.2 mg,
0.1 mmol). After 2 h, saturated, aqueous, NH4Cl was added. The
aqueous phase was extracted with EtOAc and the combined organic
extracts were washed with brine, dried (Na2SO4), and concentrated
to afford the crude product that was purified by radial chroma-
tography (8:92 to 40:60, EtOAc/hexanes) to afford 11.6 mg (54%) of
59 spectrally identical to material isolated previously and 7.4 mg
(34%) of 68 as an oil. IR (film) 3476.0, 3077.4, 2228.2, 1641.9 cmꢀ1
1H NMR (500 MHz, CDCl3)
;
d
1.24 (d, J¼2.0 Hz, 3H), 1.26–1.33 (m,
2H), 1.58 (d, J¼2.0 Hz, 1H), 1.68–2.02 (m, 7H), 1.78 (s, 3H), 2.09–2.12
(m, 1H), 2.26–2.30 (m, 1H), 2.98 (d, J¼8.7 Hz, 1H), 4.69 (s, 1H), 5.01
(s, 1H); 13C NMR (125 MHz, CDCl3)
d 19.8, 21.7, 25.3, 27.0, 29.5, 31.9,
39.2, 46.6, 51.5, 53.8, 70.6, 113.7, 125.3, 146.0.
8. Typically the C–CN bond lengths (1.36–1.40 Å) are close to those found in
benzene derivatives (1.38 Å): Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer,
L.; Orpen, A. G.; Taylor, R. J. Chem. Soc., Perkin Trans. 2 1987, 1.
9. Nitriles are powerful inductive stabilizing groups with weak delocalizing
effects: (a) See Ref. 7a; (b) See Ref. 7b; (c) See Ref. 7c.
10. Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 9330; Culkin, D. A.;
Hartwig, J. F. Organometallics 2004, 23, 3398.
11. Fluxional mixtures of N- and C-metalated nitriles are observed in some in-
stances: Sott, R.; Granander, J.; Hilmersson, G. J. Am. Chem. Soc. 2004, 126, 6798.
12. (a) Carlier, P. R.; Lo, C. W.-S. J. Am. Chem. Soc. 2000, 122, 12819; (b) Carlier, P. R.;
Lucht, B. L.; Collum, D. B. J. Am. Chem. Soc. 1994, 116, 11602.
13. Fleming, F. F.; Zhang, Z.; Liu, W.; Knochel, P. J. Org. Chem. 2005, 70, 2200.
14. Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135.
15. Fleming, F. F.; Shook, B. C. J. Org. Chem. 2002, 67, 2885.
16. Bradamante, S.; Pagani, G. A. Adv. Carbanion Chem. 1996, 2, 189.
17. (a) Walborsky, H. M.; Motes, J. M. J. Am. Chem. Soc. 1970, 92, 2445; (b) For an
excellent extension, see: Carlier, P. R.; Zhang, Y. Org. Lett. 2007, 9, 1319.
18. Hoz, S.; Aurbach, D. J. Am. Chem. Soc. 1980, 102, 2340.
4.3.34. 7a-Cyano-octahydro-4-methyl-1-(prop-1-en-2-yl)-1H-
inden-4-yl 4-nitrobenzoate (66)
A hexanes solution (0.04 mL) of BuLi (0.1 mmol) was added,
dropwise, to a ꢀ78 ꢁC THF solution (1.0 mL) of 68 (21.2 mg,
0.1 mmol). After 10 min, a THF solution (1.0 mL) of PNBCl (19.8 mg,
0.1 mmol) was added dropwise. The mixture was refluxed for 5 h,
cooled to room temperature, and then saturated aqueous NH4Cl
(2 mL) was added, the aqueous phase was extracted with EtOAc,
and the combined organic extracts were washed with brine, dried
(Na2SO4), and then concentrated. Purification by radial chroma-
tography (8:92, EtOAc/hexanes) afforded 21.8 mg (61%) of 66 as
a solid (mp 103–105 ꢁC), whose structure was unequivocally de-
termined by X-ray diffraction. IR (film) 2227.9, 1714.2 cmꢀ1 1H
;

7488
F.F. Fleming et al. / Tetrahedron 64 (2008) 7477–7488
19. Subsequent approaches to chiral metalated nitriles have employed non-
covalently linked chiral additives: (a) Suto, Y.; Kumagai, N.; Matsunaga, S.;
Kanai, M.; Shibasaki, M. Org. Lett. 2003, 5, 3147; (b) Carlier, P. R.; Lam, W. W.-
F.; Wan, N. C.; Williams, I. D. Angew. Chem., Int. Ed. 1998, 37, 2252; (c) Kuwano,
R.; Miyazaki, H.; Ito, Y. Chem. Commun. 1998, 71; (d) Soai, K.; Hirose, Y.; Sa-
kata, S. Tetrahedron: Asymmetry 1992, 3, 677; (e) Soai, K.; Mukaiyama, T. Bull.
Chem. Soc. Jpn. 1979, 52, 3371; For metalated nitriles containing chiral
auxiliaries, see: (f) Enders, D.; Shilvock, J. P.; Raabe, G. J. Chem. Soc., Perkin
37. cis-Decalin 20 exhibited spectral data identical to that of material previously
synthesized and shown to have the cis-stereochemistry: Fleming, F. F.; Zhiyu,
Z.; Wang, Q.; Steward, O. W. Org. Lett. 2002, 4, 2493.
38. Bernady, K. F.; Poletto, J. F.; Nocera, J.; Mirando, P.; Schaub, R. E.; Weiss, M. J. J.
Org. Chem. 1980, 45, 4702.
39. Fleming, F. F.; Zhang, Z.; Wang, Q.; Steward, O. W. Angew. Chem., Int. Ed. 2004,
43, 1126.
40. These conditions were found to be far superior to the use of LiHMDS in
a PhCH3/THF solvent mixture employed in an analogous cyclization.29
41. Sumrell, G. J. Org. Chem. 1954, 19, 817.
´
Trans. 1 1999, 1617; (g) Roux, M.-C.; Patel, S.; Merienne, C.; Morgant, G.;
Wartski, L. Bull. Chem. Soc. Fr. 1997, 134, 809; (h) Schrader, T. Chem.dEur. J.
1997, 3, 1273; (i) Enders, D.; Kirchhoff, J.; Lausberg, V. Liebigs Ann. 1996, 1361;
(j) Roux, M.-C.; Wartski, L.; Nierlich, M.; Lance, M. Tetrahedron 1996, 52,
10083; (k) Enders, D.; Kirchhoff, J.; Mannes, D.; Raabe, G. Synthesis 1995, 659;
42. Klumpp, G. W. Recl. Trav. Chim. Pays-Bas 1986, 105, 1.
43. Tilstam, U.; Weinmann, H. Org. Process Res. Dev. 2002, 6, 906.
44. Watkins, E. K.; Richey, H. G. Organometallics 1992, 11, 3785.
45. The authors have deposited the crystallographic data with the Cambridge
Crystallographic Data Center. The data can be obtained, on request, from the
Director, Cambridge Crystallographic Data Center, 12 Union Road, Cambridge
CB2 1EZ, UK.
´
´
˜
(l) Cativiela, C.; Dıaz-de-Villegas, M. D.; Galvez, J. A.; Lapena, Y. Tetrahedron
1995, 51, 5921; (m) Cativiela, C.; Dı´az-de-Villegas, M. D.; Ga´lvez, J. A. J. Org.
Chem. 1994, 59, 2497; (n) Enders, D.; Mannes, D.; Raabe, G. Synlett 1992, 837;
(o) Enders, D.; Gerdes, P.; Kipphardt, H. Angew. Chem., Int. Ed. Engl. 1990, 29,
179; (p) Hanamoto, T.; Katsuki, T.; Yamaguchi, M. Tetrahedron Lett. 1986, 27,
2463; (q) Marco, J. L.; Royer, J.; Husson, H.-P. Tetrahedron Lett. 1985, 26, 3567;
(r) Enders, D.; Lotter, H.; Maigrot, N.; Mazaleyrat, J.-P.; Welvart, Z. Nouv. J.
Chim. 1984, 8, 747.
46. See Ref. 36.
47. For related cyclizations of hydroxynitriles, see: (a) Aplander, K.; Hidestal, O.;
Katebzadeh, K.; Lindstroem, U. M. Green Chem. 2006, 8, 22; (b) Nicolaou, K. C.;
Baran, P. S.; Zhong, Y.-L.; Fong, K. C.; Choi, H.-S. J. Am. Chem. Soc. 2002, 124, 2190;
(c) Rouillard, A.; Deslongchamps, P. Tetrahedron 2002, 58, 6555; (d) Darvesh, S.;
Grant, A. S.; MaGee, D. I.; Valenta, Z. Can. J. Chem. 1991, 69, 723; (e) Darvesh, S.;
Grant, A. S.; MaGee, D. I.; Valenta, Z. Can. J. Chem. 1989, 67, 2237; (f) Fisher, M. J.;
Hehre, W. J.; Kahn, S. D.; Overman, L. E. J. Am. Chem. Soc. 1988, 110, 4625; (g)
Kwok, R.; Wolff, M. E. J. Org. Chem. 1963, 28, 423; (h) Holbert, G. W.; Johnston,
J. O.; Metcalf, B. W. Tetrahedron Lett. 1985, 26, 1137.
20. (a) Carlier, P. R. Chirality 2003, 15, 340; (b) Kasatkin, A. N.; Whithy, R. J. Tetra-
hedron Lett. 2000, 41, 6201 The inversion barrier for analogous C-magnesiated
cyclopropylcarbonitrile is considerably higher.17
.
21. Chelation of nitriles by lithium cations is directly analagous to the chelation of
organolithiums with proximal alkenes and aromatic systems: (a) Harris, C. R.;
p
Danishefsky, S. J. J. Org. Chem. 1999, 64, 8434; (b) Ro¨lle, T.; Hoffmann, R. W. J.
Chem. Soc., Perkin Trans. 2 1995, 1953; (c) Bailey, W. F.; Khanolkar, A. D.;
Gavaskar, K.; Ovaska, T. V.; Rossi, K.; Thiel, Y.; Wiberg, K. B. J. Am. Chem. Soc.
1991, 113, 5720.
48. Formation of lactone 30 establishes the trans-decalin ring-junction
stereochemistry.
49. The relative stabilities of cis- and trans-hydrindanes depends on temperature
and substitution pattern, with angularly substituted cis-hydrindanes generally
being more stable than their trans-hydrindane counterparts: (a) Eliel, E. L.;
Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds; Wiley: New
York, NY, 1994, pp 774–775; (b) Jankowski, P.; Marczak, S.; Wicha, J. Tetrahedron
1998, 54, 12071.
50. Chlorination with Ph3P and CCl4 afforded chloride 43 accompanied by signifi-
cant amounts of a material tentatively identified as the ether resulting from
internal alcohol attack onto the intermediate phosphonium salt.
51. Addition of HMPA to the dilithiated nitrile affords 45 (40%) despite HMPA
22. Fleming, F. F.; Vu, V. A.; Shook, B. C.; Raman, M.; Steward, O. W. J. Org. Chem.
2007, 72, 1431.
23. Metalated nitriles are more electron rich than their neutral parent nitriles: (a)
Wu, F.; Foley, S. R.; Burns, C. T.; Jordan, R. F. J. Am. Chem. Soc. 2005, 127, 1841; (b)
Groux, L. F.; Weiss, T.; Reddy, D. N.; Chase, P. A.; Piers, W. E.; Ziegler, T.; Parvez,
M.; Benet-Buchholz, J. J. Am. Chem. Soc. 2005, 127, 1854.
24. (a) Davis, F. A.; Mohanty, P. K. J. Org. Chem. 2002, 67, 1290; (b) Davis, F. A.;
Mohanty, P. K.; Burns, D. M.; Andemichael, Y. W. Org. Lett. 2000, 2, 3901; (c)
Schrader, T.; Kirsten, C.; Herm, M. Phosphorus, Sulfur Silicon Relat. Elem. 1999,
144–146, 161; (d) Gmeiner, P.; Hummel, E.; Haubmann, C. Liebigs Ann. 1995,
1987; (e) Murray, A. W.; Murray, N. D.; Reid, R. G. J. Chem. Soc., Chem. Commun.
1986, 1230.
25. (a) Spivey, A. C.; Shukla, L.; Hayler, J. F. Org. Lett. 2007, 9, 891; (b) Hu, Y.;
Bishop, R. L.; Luxenburger, A.; Dong, S.; Paquette, L. A. Org. Lett. 2006, 8, 2735;
(c) Stork, G.; Gardner, J. O.; Boeckman, R. K., Jr.; Parker, K. A. J. Am. Chem. Soc.
1973, 95, 2014; (d) Stork, G.; Boeckman, R. K., Jr. J. Am. Chem. Soc. 1973, 95,
2016.
efficiently sequestering lithium cations to selectively generate a
p-complexed
carbanion in a very similar cyclization.22
52. Knochel, P.; Dohle, W.; Kneisel, F. F.; Korn, T.; Vu, V. A. Angew. Chem., Int. Ed.
2003, 42, 4302.
53. The identity of the lactone was unequivocally determined by X-ray
crystallography.
54. Conclusive assignment of the ring-junction stereochemistry was secured by
X-ray crystallographic analysis of 54a.45
ˆ
26. For a preliminary communication, see: Fleming, F. F.; Wei, Y.; Liu, W.; Zhang, Z.
Org. Lett. 2007, 9, 2733.
27. Fleming, F. F.; Zhang, Z.; Wei, G. Synthesis 2005, 3179.
28. (a) Swiss, K. A.; Liotta, D. C.; Maryanoff, C. A. J. Am. Chem. Soc. 1990, 112, 9393;
(b) Turova, N. Y.; Turevskaya, E. P. J. Organomet. Chem. 1972, 42, 9.
29. Fleming, F. F.; Zhang, Z.; Wang, Q.; Steward, O. W. J. Org. Chem. 2003, 68, 7646.
30. Fleming, F. F.; Wang, Q. Chem. Rev. 2003, 103, 2035.
31. Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801.
32. Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307.
33. (a) See Ref. 28a; (b) See Ref. 28b.
55. Larcheveque, M.; Debal, A. Synth. Commun. 1980, 10, 49.
56. The stereochemical assignments of cis- and trans-bicyclo[5.4.0]undecanes 53b
and 54b are based on diagnostic 13C chemical shift comparisons with those of
the corresponding decalins.
57. Magid, R. M. Tetrahedron 1980, 36, 1901.
58. X-ray crystallography45 identifies a ring-flipped conformation for 60 in the
solid state, presumably to compensate for the steric crowding between the
isopropyl and hydroxyl groups. The same conformation is likely present in
solution, as gauged by the diagnostic downfield shift of the 1H NMR signal for
quaternary methyl group.
34. Grignard reagents tend to react with alkylnitriles causing deprotonation and
addition: Reynolds, G. A.; Humphlett, W. J.; Swamer, F. W.; Hauser, C. R. J. Org.
Chem. 1950, 16, 165.
35. Fleming, F. F.; Zhang, Z.; Wei, G.; Steward, O. W. J. Org. Chem. 2006, 71, 1430.
36. For an excellent overview of terms, steric constraints, and orbital overlap, see:
Gawley, R. E. Tetrahedron Lett. 1999, 40, 4297.
60. See Ref. 36.
61. Kirby, A. J. StereoelectronicEffects; Oxford University Press:Oxford,1996, pp38–40.
62. Anh, N. T.; Thanh, B. T.; Thao, H. H.; N’Guessan, Y. T. New J. Chem. 1994, 18, 489.
63. See Ref. 29.
64. Fleming, F. F.; Wang, Q.; Zhiyu, Z.; Steward, O. W. J. Org. Chem. 2002, 67, 5953.
65. See Ref. 27.