Effect of double-bond substituents on the rate of cyclization of α-carbomethoxyhex-5-enyl radicals

Article abstract of DOI:10.1021/jo402499w

Rate constants have been calculated, and compared with experimental results, for the cyclizations of 1-carbomethoxy-1-methyl-5-hexenyl radicals (2) with various substituents on C6. The calculations have been done by DFT at the B3LYP/6-311++G* level of theory. They show considerable interaction between C5 and the radical centers even in the ground state of all of the radicals 2. Experimentally, the radicals have been generated by H ^? transfer to the corresponding acrylate esters 1 and the yields of cyclized products compared to the calculated rate constants. (The cyclized products include those from cyclohydrogenation, 4, and those from cycloisomerization, 9.) Two phenyl substituents on C6 (2i), or a phenyl and a methyl substituent (2g, 2h), increase the rate of cyclization, but a single phenyl substituent on C6 produces a greater increase. The calculations show that the two phenyl substituents are twisted in the transition state for cyclization, while a single phenyl substituent remains flat in that transition state. A methyl substituent on C6 along with a single phenyl causes the phenyl to twist in the transition state and decreases the rate constant for cyclization below that of the H/Ph-substituted 2e, 2f.

Full text of DOI:10.1021/jo402499w

Article
pubs.acs.org/joc
Effect of Double-Bond Substituents on the Rate of Cyclization of
α‑Carbomethoxyhex-5-enyl Radicals
Arthur Han,† Tudor Spataru,†,‡ John Hartung,† Gang Li,† and Jack R. Norton*,†
†Department of Chemistry, Columbia University, 3000 Broadway, New York, New York 10027, United States
‡Natural Sciences Department, Hostos Community College, 500 Grand Concorse, New York, New York 10451, United States
S
* Supporting Information
ABSTRACT: Rate constants have been calculated, and compared
with experimental results, for the cyclizations of 1-carbomethoxy-1-
methyl-5-hexenyl radicals (2) with various substituents on C6. The
calculations have been done by DFT at the B3LYP/6-311++G** level
of theory. They show considerable interaction between C5 and the
radical centers even in the ground state of all of the radicals 2.
Experimentally, the radicals have been generated by H• transfer to the
corresponding acrylate esters 1 and the yields of cyclized products
compared to the calculated rate constants. (The “cyclized products”
include those from cyclohydrogenation, 4, and those from cyclo-
isomerization, 9.) Two phenyl substituents on C6 (2i), or a phenyl
and a methyl substituent (2g, 2h), increase the rate of cyclization, but
a single phenyl substituent on C6 produces a greater increase. The
calculations show that the two phenyl substituents are twisted in the transition state for cyclization, while a single phenyl
substituent remains flat in that transition state. A methyl substituent on C6 along with a single phenyl causes the phenyl to twist
in the transition state and decreases the rate constant for cyclization below that of the H/Ph-substituted 2e, 2f.
INTRODUCTION
■
Radical cyclizations have been used extensively in synthesis.1−3
They are tolerant of functional groups and can be carried out
under mild conditions. However, they have generally involved
the stoichiometric use of Bu3SnH and of a heavy element X
(often Br or I, sometimes Cl, PhSe, or PhS) that is easily
abstracted by Bu3Sn• radicals. Such methods are obviously not
“atom-economical” and frequently leave toxic levels of tin
compounds in the products.
We have explored H• transfer to olefins from transition
metals as an alternative method of generating carbon-centered
radicals. We have found that CpCr(CO)3H carries out such
•
transfers and can be regenerated from CpCr(CO)3 under
modest H2 pressures (eq 1)4 and that Co(dmgBF2)2(H2O)2
gives transferable H• from H2 under similar conditions (eq 2).5
Both reactions are catalytic and far more atom-economical than
traditional methods. Effective use of our reaction, however,
requires not only a respectable rate of H• transfer from M−H
to the substrate 1 (ktr) but also a rate of cyclization kcyc that
competes with hydrogenation (kH[M−H]) and isomerization
(kiso[M•]). As Scheme 1 makes apparent, the yield will be a
function of kcyc vs (kH[M − H] + kiso[M•]).
Yang reported DFT calculations on such radicals (7) with a
variety of substituents E and R.8 We therefore began with two
Newcomb and co-workers reported experimental rate
constants for the cyclization of the related (ethyl esters)
phenyl substituents on the b double bond of the substrate 1,
giving us two radical-stabilizing phenyl substituents (R1 = R2 =
diphenyl-substituted radicals 7a,b to the corresponding radicals
8 (easily monitored by their strong absorbance at 335 nm).6
(They also reported an experimental rate constant for the
Received: November 19, 2013
Published: February 7, 2014
cyclization of the ethyl ester of 2a.7) Later Guan, Phillips, and
© 2014 American Chemical Society
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Scheme 1. Pathways Available for an α-Carbomethoxy Radical 2
gap is large. For substrates containing conjugated double bonds,
CASSCF (MCSCF) calculations with various numbers of occupied
and unoccupied orbitals taken into their “active space” were carried
out to check for CI interactions and for charge transfer from occupied
to empty orbitals; these calculations did not show any significant
charge transfer.
Ph, 2i) on C6 of the radical 2. We expected 2i to cyclize
quickly, and it did.4a However, mindful of Curran’s remark2d
that “most substituents accelerate 5-exo cyclizations”, we have
now sought to quantify, both theoretically and experimentally,
kcyc for substrates that bear different radical-stabilizing
substituents on the b double bond. We have thus been able
to generate radicals 2 that cyclize more rapidly than 2i.
RESULTS AND DISCUSSION
■
Substituted hexenyl radicals 2a−i can adopt an “open” or a
“chair” conformation.15
Houk9 and others8a,10 have shown that DFT, in particular
with the B3LYP functional, is useful in predicting the rate
constants of various radical reactions, including cyclizations and
retrocyclizations. We have therefore calculated kcyc for the
acrylates below, with different substituents R1 and R2 on the b
double bonds. These calculations, and the corresponding
experiments in which these radicals are generated by H•
transfer from CpCr(CO)3H, should enable synthetic chemists
to design substrates with confidence.
B3LYP/6-311++G** DFT calculations imply that these
radicals are unstrained when open, with C−C−C angles
(around the saturated carbons C2, C3, and C4) equal or very
close to tetrahedral (109.5°). Such calculations do suggest
considerable strain in their chair forms, with the C−C−C
angles increased to around 115°. However, at room temper-
ature the calculated energies of the open forms of these radicals
are approximately equal to those of their chair forms. Similar
calculations on the hydrogenation product 5 show its chair
form to be 7 kcal/mol higher in energy than its open form,
implying that the chair forms of the radicals 2 have strain
energies around 7 kcal/mol. To understand how the electronic
stabilization of these chair forms of 2 offsets their strain
energies we must consider their molecular orbitals (Figure 1).
Figure 1 shows the surfaces of the HOMO, the highest fully
occupied orbital, for the chair forms of the radical 2a (with no
substituents on C6) and the radical 2d (with two methyl
substituents on C6). The surfaces of HOMO for 2b,c and 2e−i
have similar features. It is apparent in Figure 1 that there is a
strong bonding interaction between C1 and C5 (the carbons to
be bonded by cyclization), although there is no formal σ bond
between them and the distance between them is large. This
interaction stabilizes the chair structures but introduces strain
(and the 115° C−C−C angles).
The calculated distance in the chair between C1 and C5 is
equal to 3.23 Å for radical 2a and 3.20 Å for radical 2d, twice
the length of a normal carbon−carbon single bond. A similar
interaction, with an even shorter distance (3.11 Å), is implied
by DFT calculations on the related primary radical 7.8a The
result is some pyramidalization. For example, in the initial chair
of 2i the C5−C1−CH3 angle increases to 95.65°, while the
C5−C1−CO2Me angle increases to 101.22°; more pyramidal-
ization is observed at C5, where the C1−C5−C6 angle
becomes essentially tetrahedral (110.79°).
COMPUTATIONAL DETAILS
■
The calculations were performed with the Gaussian0311 and 0912
suites of programs. There is precedent for the use of the 6-31G*, 6-
31+G*, and 6-31+G** basis sets in DFT calculations on radical
cyclizations8a,10c,e and retrocyclizations.9b Coote and co-workers have
questioned the ability of DFT methods to provide accurate energetics
for radical reactions,13 while Fleurat−Lessard and co-workers have
shown that B3LYP gives qualitatively inaccurate results for two
nonradical organic reactions.14 However, Fu, Liu, and co-workers,
despite admitting that “the UB3LYP method cannot accurately predict
the absolute free energy barriers”, have argued that “it can reliably
predict the relative free energy barriers”.10e We have tested two
functionals (BP86 and B3LYP) with two basis sets (6-31G* and 6-
311++G**) in the calculation of the rate constants for our
cyclizations. A combination of B3LYP and 6-311++G** gave the
most reasonable results (relative rate constants like those implied by
our yields of cyclized products), presumably because α-carbomethoxy
radicals only contain light atoms and their HOMO−LUMO energy
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Figure 1. HOMO surfaces calculated for 2a (the Z, β rotamer) and 2d
(the Z, β rotamer). The lower drawings (B) have an electron density
isovalue limit of 0.02 au (normal); the upper drawings (A) have an
electron density isovalue limit of 0.04 au.
Table 2. Calculated Rate Constants (Gaussian 03, B3LYP,
and 6-311++G**) for Cyclization of Each Conformation (α
and β) of α-Carbomethoxy Radicals (Z)-2 at 298 K
compd kα, s−1 (ΔG⧧, kcal/mol) kβ, s−1 (ΔG⧧, kcal/mol) K = [α]/[β]
Resonance leads to restricted rotation about the C1−CO2Me
bond in the radicals 2, so they exist as Z-2 (with resonance
structure Z-2′) and E-2 (with resonance structure E-2′). The
rates at which such conformers interconvert were studied some
time ago by Fischer and co-workers.16 More recently,
Newcomb and co-workers considered the relationship between
such conformational interconversions and the rates at which
carboalkoxy-substituted radicals cyclize6a and concluded that
interconversion is faster than cyclization for tertiary radicals like
2. Our DFT calculations show a barrier to E/Z interconversion
<5 kcal/mol for 2i (see Figure 2 below) and imply a similar
barrier for other radicals 2.
Z-2a
Z-2b
Z-2c
Z-2d
Z-2e
Z-2f
Z-2g
Z-2h
Z-2i
9.35 × 102 (13.40)
4.39 × 103 (12.48)
1.61 × 103 (13.08)
2.33 × 103 (12.86)
1.18 × 106 (9.07)
8.84 × 104 (10.71)
6.56 × 104 (10.88)
4.05 × 103 (12.53)
7.81 × 103 (12.14)
2.24 × 102 (14.25)
5.42 × 102 (13.72)
1.90 × 102 (14.35)
9.80 × 102 (13.37)
2.60 × 104 (11.43)
3.52 × 104 (11.25)
3.39 × 103 (12.64)
2.80 × 102 (14.12)
0.30
0.14
0.088
0.18
0.18
0.95
0.25
0.47
a
a
2.71 × 104 (11.41)
0.26
a
See ref 15.
C−CO2Me and C1−C2 bonds. The barrier to rotation about
C1−C2 is larger.
Figure 2. Rotamers of radical 2i and barriers to their interconversion
(calculated with Gaussian 09, B3LYP, and 6-311++G**). The C1−C5
distance must increase temporarily during rotation about either the
C1−CO2Me bond or the C1−C2 bond.
For 2a−i we took the Z conformers and calculated the
energies of their α and β orientations about the C1−C2 bond,
which gave us the relative populations in Table 1. The β
orientation is favored in all cases.
From our calculated barriers for 2i we believe that the
interconversion of the α and β orientations is always fast
relative to cyclization (for which the barrier is over 10 kcal/
mol). This situation, with the free energy surface illustrated in
Figure 3, thus qualifies for Curtin−Hammett kinetics.18
Separate transition states, and separate kcyc, have been
calculated (Gaussian 03, B3LYP functional, 6-311++G**
basis set) for the α and β orientations of each compound 2.
The results are shown in Table 2, along with the equilibrium
constants K = α/β implied by the conformer populations in
Table 1.
The barrier to cyclization for 2i is much larger, 10.1 kcal/mol
(see Table 2), suggesting that E/Z interconversion will be facile
during cyclization of all the radicals 2a−i. For simplicity, given
that our interest is in relative cyclization rates, we have
calculated kcyc values for the Z conformer of each radical 2.
There is, however, an additional conformational issue. A
radical like 2 can exist as either of two rotamers, 2α and 2β,
about the bond between C1 and C2. (These rotamers lead to
alternate diastereomers 3α and 3β upon cyclization.) For 2i, we
have calculated (see Figure 2) the barriers to rotation about the
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The values of kcyc for 2a−i in Table 2 reflect the ability of the
substituents R1 and R2 to stabilize the cyclized radicals 3a−i.
Replacing the hydrogens on C6 in 2a by carbon substituents
increases the interaction between C1 and C5 in the HOMO, as
can be seen in Figure 1 (above). The HOMO surfaces for 2a
and 2c are shown with the standard 0.02 au electron density
isovalue limit in the lower section, B, and then with an isovalue
limit of 0.04 au in the upper section, A. For 2a there is no
interaction between C1 and C5 at isovalue limits equal to or
greater than 0.04 (section A), while for 2b−i there is
interaction between C1 and C5 in both sections.
Figure 4 shows the π energy levels of radicals 2 with
symmetric substituents on the b double bond (2a, R1 = R2 = H;
2d, R1 = R2 = CH3; and 2i, R1 = R2 = Ph). The radical center in
2 is sufficiently electrophilic that the most important interaction
of its SOMO during its cyclization is with its HOMO. As
radical-stabilizing substituents are added to C6, the HOMO
rises, the HOMO−LUMO and HOMO−SOMO energy
differences decrease, the barrier to cyclization decreases, and
kcyc increases. If we compare 2a with 2d in Figure 4, we can see
that methyl substituents ought to produce a slight increase in
the calculated kcyc, and we see a slight increase in Table 2. If we
compare 2a with 2i in Figure 4, we can see that aromatic
substituents ought to produce a much larger increase in the
calculated kcyc, and we see a large increase in Table 2.
Table 1. Calculated Populations (Gaussian 03, B3LYP, and
6-311++G**) of the α and β Conformers for Z-2 at 298 K
R1
R2
α
β
2a
2b
2c
2d
2e
2f
H
H
23.0
11.9
8.1
77.0
88.1
91.9
84.5
84.5
51.4
80.2
67.9
79.1
Me
H
H
Me
Me
H
Me
Ph
H
15.5
15.5
48.6
19.8
32.1
20.9
Ph
Me
Ph
Ph
2g
2h
Ph
Me
Ph
a
2i
a
See ref 17.
The effect of C6 substituents on the cyclization of primary
hex-5-enyl radicals has been extensively investigated. Most
substituents have little effect on kcyc: two methyl substituents
increase it by a factor of only 2.4,19 while two fluorine
substituents decrease it slightly.20 On the other hand, two
phenyl substituents increase it by a factor of over 200.21
We expected similar substituent effects on the cyclization of
our tertiary α-carbomethoxy radicals 2; we expected mono-
Figure 3. Free energy surface for a typical radical 2 with rapid
interconversion of its α and β rotamers.
Figure 4. Calculated HOMO−LUMO π energy levels for the chair forms of variously substituted radicals 2. The first two columns are those of 2
with no substituents on the b double bond (2a), the middle two columns are those of 2 with two methyl substituents (2d), and the last two columns
on the right are those of 2 with two phenyl substituents (2i).
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substitution on C6 to produce an effect similar to (but smaller
than) the effect of disubstitution. The calculations in Table 2
corroborate the first prediction but not the second. A single
phenyl substituent on C6 increases the calculated kcyc by over
103 (compare kcyc for 2e with that for 2a), but the addition of a
methyl substituent decreases the calculated kcyc somewhat
(compare 2g with 2e, 2h with 2f), and the addition of a
second phenyl substituent decreases the calculated kcyc by a
factor of around 40 (compare kcyc for 2i with those for 2e, 2f).
In order to test these predictions experimentally we have
examined the product distributions from the catalytic
cyclizations of 1a,e−g,i.
A cycloisomerization, for example, that of 1g to 9g (41%),
does not consume CpCr(CO)3H. Only the hydrogenation of
•
1g (to 5, 49%) affects the [CpCr(CO)3H]/[CpCr(CO)3 ]
ratio; approximately 1 equiv of CpCr(CO)3H remains at the
end of the reaction if we begin with 2 equiv.
Table 3 gives the yields for cyclization (to 4 or 9),
hydrogenation (to 5), and isomerization (to 6).
The rate constants for the hydrogenation (kH) of 2a−i
should be little affected by substituents on C6. For a particular
substrate, with a given [CpCr(CO)3H], the relative rates of
cyclization and hydrogenation will be determined by kcyc, as
Scheme 1 implies (eq 7). Indeed, the cyclization yields for the
various substrates in Table 3 are approximately what we expect
from the calculated kcyc in Table 2. For example, the yield of 4
or 9 increases (and the yield of the hydrogenation product 5
decreases) as the calculated kcyc increases, in the order 1a < 1b
< 1d. Of course, [CpCr(CO)3H] decreases in the course of a
stoichiometric cyclization.
Cyclization of α-Carbomethoxy Radicals 2 with
Cp(CO)3CrH. We prepared the diene substrates 1a−i by the
method we had previously used for other substrates (eq 4).4a
kcyc
k
hyd[CpCr(CO)3H]
rate of formation of the cyclization product (4 or 9)
rate of formation of the hydrogenation product 5
We treated these dienes with a stoichiometric amount of
=
CpCr(CO)3H under standard conditions (benzene-d6, 323 K)
1
(7)
and quantified the products by H NMR. From substrates
without methyl substituents on C6 (1a,e,f,i) we obtained
cyclization products like 4i (eq 5), presumably arising from
In the course of a catalytic reaction [CpCr(CO)3H] will
remain approximately constant and lower than during the
stoichiometric reactions in Table 3. (Although the hydrogen in
a catalytic reaction keeps most of the Cr in the form of
CpCr(CO)3H, only 7 mol % of Cr is present.) We thus expect
higher yields of the cyclization products 4/9 under catalytic
conditions, and these are apparent in Table 4. The relative
yields in Table 4 from the various substrates show a pattern like
that in Table 3, approximately what we would expect from the
calculated rate constants in Table 2.
Why Do the Monophenyl Radicals (2e,f) Cyclize More
Quickly Than the Ph2 (2i) and the Ph(Me) (2g, 2h)
Radicals? In general, the addition of radicals to RCHCPh2 is
faster than the addition of the same radicals to RCHCHPh,
although the effect is smaller than would be expected if the
substituent effects were additive. For the cyclization of 10a, kcyc
at 20 °C is 1.9 × 105 s−1, whereas for 10b it is 3.2 × 105 s−1.23
For the cyclization of 11a, kcyc at 20 °C is 5.4 × 106 s−1, whereas
for 11b it is 1.7 × 107 s−1.24 For the addition of ambiphilic/
electrophilic radicals like (CH3)2(NC)C• (which resembles 2
transfer of a second H• to the cyclized radical 3i. However,
from substrates bearing methyl groups at C6 (1b−d or 1g,h)
we obtained unsaturated products like 9g (eq 6), presumably
the result of H• abstraction from the methyl of the cyclized
radical 3g (and of the congestion around the radical center in
3g). The conversion of 1g to 9g involves neither the gain nor
the loss of hydrogen atoms and is thus a cycloisomerization.22
Table 3. NMR Yields of the Products from Treatment of 1a,b,1d−g,i with Stoichiometric CpCr(CO)3H
a
a
R1
R2
cyclization of 4 (%)
cycloisomerization 9 (%)
hydrogenation 5 (%)
isomerization 6 (%)
1a
1b
1d
1e
1f
H
H
5
0
0
16
18
0
76
56
51
37
38
49
55
19
28
31
11
9
Me
Me
Ph
H
H
Me
H
0
52
53
0
Ph
Me
Ph
0
1g
1i
Ph
Ph
41
0
10
18
27
a
Combined yields of both diastereomers.
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Table 4. Isolated Yields of Cyclization Products from the
Treatment of 1a,b,d−g,i with Catalytic Amounts of
CpCr(CO)3H under H2
a
a
R1
R2
cyclization 4 (%)
cycloisomerization 9 (%)
1a
1b
1d
1e
1f
H
H
10
0
0
42
45
0
Me
Me
Ph
H
H
Me
H
0
97
92
0
Figure 5. Definition of “twist angle” for one of the phenyl rings in
benzophenone.
Ph
Me
Ph
0
1g
1i
Ph
Ph
74
0
71
Such twisting has also been found by EPR for two phenyl
substituents on a radical center, i.e., for 1,1-diphenylethyl
radicals like the one shown (M = a variety of group 4
elements).27 (At low temperature, the H’s pictured are
inequivalent.) A twist angle of 22° was obtained for
benzophenone ketyl by early ab initio calculations.28
a
Combined yields of both diastereomers.
electronically) to CH2CHPh the rate constant is 2410 M−1
s−1 at 315 K, whereas for the same addition to CH2CPh2 the
rate constant is 7010 M−1 s−1.10a
The twisting of two phenyl substituents on a radical center is
responsible for the decrease between the effect of the first
phenyl substituent and the effect of the second on the C−H
bond strengths below.29 (Halgren, Roberts, Newcomb and co-
workers have also noted the differential effect of Ph substitution
on C−H bond strengths.24)
However, the yield of the cyclized product 4 in Tables 3 and
4 is higher with one Ph (substrates 1e,f) than with two
(substrate 1i), in agreement with the calculated k values in
Table 2 for 2e and 2f vs 2i. The higher yields suggest faster kcyc,
consistent with the implications of our DFT calculations.
The lack of substituent additivity in all these reactions
presumably arises from the gearing of two phenyls on the same
carbon. For example, neither phenyl is coplanar with the radical
center in the cyclized radical 3i, whereas planarity and
stabilization are easily achieved by the single phenyl substituent
in 3e and 3f.
•
CH3−H ⇌ CH3 + H (105.0 kcal/mol)
•
PhCH2−H ⇌ PhCH2 + H (88.5 kcal/mol)
Ph2CH−H ⇌ Ph2CH• + H (84.5 kcal/mol)
With our radicals 2 we expect twisting to decrease as
cyclization begins and the C5−C6 bond lengthens; it should,
however, remain substantial. Our calculations predict a large
twist angle in 2i itself (an average of 51.9° for the two phenyls),
which decreases as cyclization begins (and C5−C6 lengthens)
but remains substantial in the transition state in Figure 6 (an
average of 41.3°) and in the cyclized radical 3i (an average of
36.1°).
Similar but smaller twists are found in the transition state for
the cyclization of the 6,6-diphenyl carbethoxy-substituted
hexenyl radical 7a, the subject of DFT calculations by Phillips
et al.8a From their results, we compute an average twist angle
for the two phenyls of 46.7° in the initial radical, an average
angle of 40.4° in the transition state, and an average angle of
31.9° in the cyclized radical 8a. (They considered only cases
with two phenyl substituents on C6.)
Why is the Ph2/Ph(H) effect so large in our cyclizations that
Ph(H) (2e,f) is now faster than Ph2 (2i) in the radicals 2? The
Newcomb aminyl radicals 10 resemble secondary carbon
radicals, the Newcomb radicals 11 are primary, and the radicals
in the Fischer−Radom table are secondary and primary. The
radicals 2 are tertiary and thus more sensitive (when forming
the C1−C5 bond) to repulsion by twisted phenyl substituents
on C6. The C1−C5 distance in the transition state for the
The interaction of two phenyl rings attached to the same sp2
carbon is illustrated by the X-ray structures of Ph2CO and
Ph2CCH2 and their derivatives. Benzophenone (which exists
in two different crystalline forms) shows an average twist angle
of 33°.25 (We define the “twist angle” as the angle between the
normal to the purple phenyl ring plane and the normal to the
pink “carbonyl plane” in Figure 5.) Various para-substituted
derivatives of 1,1-diphenylethylene show twist angles averaging
39°.26 The diphenylethylene derivatives have larger twist angles
because of repulsion between the ethylenic hydrogens and the
ortho hydrogens on the phenyl rings. These precedents suggest
a considerable twist of the two phenyl substituents in our
substrate 1i, which our DFT calculations confirm.
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inert argon atmosphere glovebox (O2 <1 ppm). Reaction mixtures
1
involving CpCr(CO)3H were all prepared in the glovebox. H NMR
and 13C NMR spectra were recorded at ambient temperature (298 K)
at 500, 400, or 300 MHz and 125, 100, or 75 MHz, respectively. High-
resolution mass spectra were acquired (after ionization by EI) by peak
matching on a double-focusing magnetic sector instrument.
General Method for the Synthesis of Diene Substrates
1a,b,d−g,i. The synthesis of substrates followed a known procedure
(eq 5).4a To a solution of LDA in THF was added methyl-3-
(dimethylamino)propionate (1.1 mmol) dropwise at −78 °C. The
mixture was stirred for 0.5 h before the addition of a solution of alkyl
halide (1 mmol) in THF and freshly distilled HMPA (1 mmol). The
mixture was then warmed to room temperature, stirred for 48 h,
quenched with saturated NH4Cl, and extracted with Et2O. The extract
was dried over MgSO4, filtered, concentrated, and taken up in 5 mL
MeOH, and excess MeI (13 mmol) was added; the flask was wrapped
in foil and the mixture stirred overnight (16−18 h). After
concentration in vacuo, the residue was washed with Et2O three
times; removal of the remaining solvent afforded the ammonium
iodide salt as a bright yellow solid. Benzene (20 mL) was then added,
along with excess DBN (2 mL), and the bright yellow mixture was
stirred at reflux for 4 h. After being cooled to room temperature, the
solution was washed with 1 N HCl, and Et2O was added. The
collected organic layers were washed with brine, dried over MgSO4,
filtered, and concentrated. Flash chromatography (10% EtOAc/
hexanes) on silica gel afforded the desired 1,6-diene.
Methyl 2-Methylenehept-6-enoate (1a). Compound 1a was
prepared in 28% yield (43 mg) over three steps from 1 mmol of 5-
iodopent-1-ene as a bright yellow oil. Spectroscopic data matched the
literature.30
Figure 6. Two views of the transition state for cyclization by radicals
2e and 2i; oxygen atoms are red, C1, C5, and C6 are blue. In the
transition state for 2e the C1−C5 distance is 2.22 Å and the C5−C6
distance is 1.39 Å; in that for 2i C1−C5 is 2.22 Å and C5−C6 is 1.40
Å.
Methyl 2-Methyleneoct-6-enoate (1b). Compound 1b was
prepared in 55% yield (91 mg) over three steps from 1 mmol of
(E)-6-iodohex-2-ene31 as a golden yellow oil: H NMR (400 MHz,
1
CDCl3) δ 6.13 (s, 1 H), 5.52 (s, 1 H), 5.43 (d, J = 3.9 Hz, 2 H), 3.75
(s, 3 H), 2.30 (t, J = 7.6 Hz, 2H), 2.06−1.93 (m, 2 H), 1.65 (s, 3 H),
1.52 (qn, 2 H); 13C NMR (100 MHz, CDCl3) δ 167.8, 140.7, 130.9,
125.3, 124.6, 51.8, 32.1, 31.4, 28.3, 17.9; IR (neat) 2932, 2859, 1725,
1632 cm−1; HRMS (FAB+) calcd for C10H16O2 [M]+ 168.1150, found
168.1149.
Methyl 7-Methyl-2-methyleneoct-6-enoate (1d). Compound 1d
was prepared in 65% yield (59 mg) over three steps from 0.5 mmol of
6-iodo-2-methylhex-2-ene32 as a golden yellow oil: 1H NMR (500
MHz, CDCl3) δ 6.15 (s, 1H), 5.55 (s, 1H), 5.14 (t, J = 7.0 Hz, 1H),
3.77 (s, 3H), 2.32 (t, 2H), 2.03 (q, J = 7.2 Hz, 2H), 1.71 (s, 3H), 1.62
(s, 3H), 1.57−1.48 (qn, 2H); 13C NMR (125 MHz, CDCl3) δ 167.9,
140.8, 131.8, 124.5, 124.2, 64.5, 51.7, 31.5, 28.6, 27.6, 25.7; IR (neat)
2927, 2858, 1725, 1630 cm−1; HRMS (FAB+) calcd for C11H18O2
[M]+ 182.1307, found 182.1315.
cyclization of 2 is 0.10 Å longer for the Ph2 case (2i) than for
the H2 (2a) and Me2 (2d) cases. Note that the Ph twist is
smaller (previous paragraph) in the transition state for the
cyclization of the Newcomb/Phillips/Yang secondary hexenyl
radical 7a than for the cyclization of the tertiary radical 2i.
Twists are also found when C6 bears a methyl along with a
phenyl substituent. In the transition state for the cyclization of
Z-2g the phenyl is twisted by an average (over the α and β
rotamers) of 34°. In the transition state for the cyclization of Z-
2h the phenyl is twisted considerably more, with the angle
averaging 61° between the α and β rotamers  presumably
because the carbon chain cis to the phenyl can contribute to its
twist.
A single phenyl substituent, however, is flat in the substrates
1e (E) and 1f (Z) and remains so as 2e and 2f cyclize. It makes
cyclization more exothermic (the cyclization of the Ph1-
substituted Z-2e-α to Z-3e-α is 8.3 kcal/mol downhill, whereas
the cyclization of the Ph2-substituted Z-2i-α to Z-3i-α is only
5.1 kcal/mol downhill (both calculated with Gaussian 09,
B3LYP, and 6-311++G**). It stabilizes the transition state
substantially, and increases the rate constant for cyclization. A
similar acceleration is to be expected for any single aryl
substituent.
(E)-Methyl 2-Methylene-7-phenylhept-6-enoate (1e). Compound
1e was prepared in 39% yield (90 mg) over three steps from 1 mmol
of (E)-(5-iodopent-1-en-1-yl)benzene33 as a cloudy pale yellow oil: 1H
NMR (500 MHz, CDCl3) δ 7.33 (d, J = 7.2 Hz, 2H), 7.28 (t, J = 7.3
Hz, 2H), 7.18 (t, J = 6.8 Hz, 1H), 6.39 (d, J = 15.8 Hz, 1H), 6.27−6.17
(m, 1H), 6.16 (s, 1H), 5.55 (s, 1H), 3.74 (s, 3H), 2.36 (t, J = 7.3 Hz,
2H), 2.24 (q, J = 13.6, 6.6 Hz, 2H), 1.66 (qn, J = 14.6, 7.3 Hz, 2H);
13C NMR (125 MHz, CDCl3) δ 167.7, 140.4, 137.8, 130.34, 130.31,
128.5, 126.9, 126.0, 124.9, 51.8, 32.5, 31.5, 28.1; IR (neat) 3082, 3060,
3026, 2962, 2853, 1723, 1631, 1495 cm−1; HRMS (FAB+) calcd for
C15H18O2 [M]+ 230.1307, found 230.1314.
(Z)-Methyl 2-Methylene-7-phenylhept-6-enoate (1f). Compound
1f was prepared in 35% yield (122 mg) over three steps from 1.5
mmol of (Z)-(5-iodopent-1-en-1-yl)benzene34 as a golden yellow oil:
1H NMR (400 MHz, CDCl3) δ 7.35−7.29 (m, 2H), 7.26 (dd, J = 7.7,
1.4 Hz, 2H), 7.24−7.19 (m, 1H), 6.43 (dt, J = 11.8, 1.9 Hz, 1H), 6.11
(d, J = 1.5 Hz, 1H), 5.66 (dt, J = 11.7, 7.3 Hz, 1H), 5.48 (q, J = 1.4 Hz,
1H), 3.74 (s, 3H), 2.41−2.29 (m, 4H), 1.69−1.57 (m, 2H); 13C NMR
(125 MHz, CDCl3) δ 167.7, 140.3, 137.6, 132.3, 129.3, 128.7, 128.1,
126.5, 124.9, 51.8, 31.5, 28.6, 28.0; IR (neat) 3082, 3060, 3026, 2962,
2853, 1723, 1631, 1495 cm−1. HRMS (FAB+) calcd for C15H18O2
[M]+ 230.1307, found 230.1314.
EXPERIMENTAL SECTION
■
All reactions were carried out under an atmosphere of argon in
glassware that had been flame-dried under vacuum and backfilled with
argon. High-pressure reactions were carried out in a Fisher−Porter
bottle equipped with a pressure gauge, gas inlet, and pressure release
valve. Hexamethylphosphoramide (HMPA) was distilled from CaH2.
Deuterated benzene (C6D6) was purified by vacuum transfer from
CaH2. THF and benzene (C6H6) were distilled from sodium−
benzophenone ketyl. Et2O and CH2Cl2 were dried by filtration
through alumina. CpCr(CO)3H was stored and manipulated in an
1944
dx.doi.org/10.1021/jo402499w | J. Org. Chem. 2014, 79, 1938−1946

The Journal of Organic Chemistry
Article
(E)-Methyl 2-Methylene-7-phenyloct-6-enoate (1g). Compound
1g was prepared in 36% yield (89 mg) over three steps from 1 mmol
of (E)-(6-iodohex-2-en-2-yl)benzene as a bright yellow oil: H NMR
H), 7.21 (m, 1 H), 5.19 (s, 1 H), 5.08 (s, 1 H), 3.61 (m, 1 H), 3.15 (s,
3 H), 2.27 (m, 1 H), 2.00−1.79 (m, 3 H), 1.58 (m, 2 H), 0.94 (s, 3
H); minor: 7.29 (d, J = 8.2 Hz, 2 H), 7.25 (d, J = 3.6 Hz, 2 H), 7.21
(m, 1 H), 5.14 (s, 1 H), 5.04 (s, 1 H), 3.48 (s, 3 H), 2.96 (m, 1 H),
2.38 (m, 1 H), 2.00−1.79 (m, 5 H), 1.06 (s, 3 H); 13C NMR (125
MHz, CDCl3) δ major: 178.5, 149.0, 142.7, 128.0, 127.9, 127.2, 127.1,
127.0, 114.3, 55.4, 52.4, 51.3, 40.1, 29.3, 22.6, 18.9; minor: 176.7,
150.1, 143.9, 128.0, 127.9, 127.2, 127.1, 127.0, 113.4, 53.9, 51.0, 50.2,
37.8, 31.8, 25.6, 22.9; IR (neat) 3082, 3057, 3024, 2951, 2874, 1733,
1627, 1600, 1575, 1495 cm−1; HRMS (FAB+) calcd for C16H20O2
[M]+ 244.1442, found 244.1466.
1
(300 MHz, CDCl3) δ 7.41−7.27 (m, 4H), 7.25−7.17 (m, 1H), 6.16−
6.15 (m, 1H), 5.77 (td, J = 7.2, 1.4 Hz, 1H), 5.55 (q, J = 1.4 Hz, 1H),
3.76 (s, 3H), 2.38 (t, J = 7.5 Hz, 2H), 2.23 (q, J = 7.3 Hz, 2H), 2.03
(dd, J = 2.1, 0.8 Hz, 3H), 1.65 (qn, J = 7.5 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 167.8, 143.9, 140.5, 135.1, 128.2, 127.9, 126.5, 125.6,
124.8, 51.8, 31.6, 28.3, 28.3, 15.9; IR (neat) 2919, 2853, 1722, 1630,
1494 cm−1; HRMS (FAB+) calcd for C16H20O2 [M]+ 244.1463, found
244.1470.
General Method for Stoichiometric Cyclizations. To a J.
Young tube were added CpCr(CO)3H (50 mg, 0.13 mmol) and a
C6D6 (0.6 mL) solution of the substrate (0.06 mmol). The bright
green reaction mixture was then kept overnight (16−18 h) at 50 °C
ASSOCIATED CONTENT
■
S
* Supporting Information
All NMR (1H, 13C) spectra and calculated Cartesian
coordinates. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
before product yields were determined by H NMR.
General Method for Catalytic Cyclizations. To a Fisher−Porter
pressure apparatus were added CpCr(CO)3H and a C6H6 solution of
the substrate (0.1 M) before the apparatus was thoroughly purged with
H2 and pressurized to 3 atm. The bright green reaction mixture was
AUTHOR INFORMATION
Corresponding Author
*E-mail: jrn11@columbia.edu.
Notes
■
1
kept for 16 h at 50 °C and the reaction examined by H NMR before
being cooled to room temperature and quenched with O2. The
resulting dark green reaction mixture was filtered, concentrated, and
purified by flash chromatography on silica gel (0−10% EtOAc/
hexanes), affording the cyclized product (always a clear oil) as a
mixture of two inseparable diastereomers.
The authors declare no competing financial interest.
The structures of the isolated major and minor diastereomers of 4g
were confirmed by 2D NMR as previously reported by Pulling, Smith,
and Norton.4a The stereochemical assignments of cyclization products
4b−f are based on predictions from the Beckwith15b−Houk15c model.
Methyl 1,2-Dimethylcyclopentanecarboxylate (4a). Compound
4a was isolated as a mixture of diastereomers (61:39) in 10% yield (5
mg) from 0.3 mmol 1a. The spectroscopic data matched those in the
literature.35
ACKNOWLEDGMENTS
■
The synthetic work was supported by US Department of
Energy Grant No. DE-FG02-97ER14807 and by Boulder
Scientific and OFS Fitel. A.H. gratefully acknowledges a
́ ́
summer fellowship from the Societe de Chimie Industrielle.
J.H. is grateful to the Guthikonda family for financial support in
the form of a graduate fellowship. The computational work was
supported, in part, under National Science Foundation Grant
Nos. CNS-0958379 and CNS-0855217 to the City University
of New York High Performance Computing Center at the
College of Staten Island. Earlier work was supported by the
National Science Foundation through TeraGrid resources
provided by the TeraGrid Science Gateways program under
Grant Nos. CHE090082 and CHE100136. We thank D. P.
Estes, Y. Hu, Prof. B. Kahr, and Prof. D. Dougherty for helpful
Methyl 1-Methyl-2-vinylcyclopentanecarboxylate (9b or 9c). The
compound was isolated as a mixture of diastereomers (57:43) in 42%
1
yield (21 mg) from 0.3 mmol of 1b: H NMR (500 MHz, CDCl3) δ
major: 5.77 (p, J = 10 Hz, 1H), 5.44 (m, 1H), 5.02 (dd, 1H), 3.68 (s, 3
H), 2.88 (q, J = 10 Hz, 1H), 2.2−2.10 (m, 2H), 1.89−1.49 (m, 4H),
1.07 (s, 3 H); minor: 5.69 (p, J = 10 Hz, 1H), 5.44 (m, 1H), 4.99 (dd,
1H), 3.62 (s, 3 H), 2.51 (q, J = 10 Hz, 1H), 2.2−2.10 (m, 2H), 1.89−
1.49 (m, 4H), 1.25 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ major:
177.9, 137.5, 117.6, 52.5, 46.4, 44.3, 36.2, 31.1, 23.0, 20.3; HRMS
(FAB+) calcd for C10H16O2 [M]+ 168.1150, found 168.1155.
́
discussions on twist angle issues and Prof. A. K. Rappe for
Methyl 1-Methyl-2-(prop-1-en-2-yl)cyclopentanecarboxylate
advice on the calculational analysis of a Curtin−Hammett
(9d). Compound 9d was isolated as a mixture of diastereomers
situation.
1
(59:41) in 45% yield (33 mg) from 0.4 mmol of 1d: H NMR (500
MHz, CDCl3) δ major: 4.86 (s, 1 H), 4.70 (s, 1 H), 4.11, (t, J = 6.5
Hz, 1 H), 3.72 (s, 3 H), 2.35 (q, J = 10 Hz, 1H) 1.65 (d, J = 5 Hz,
3H); minor: 4.80 (s, 1 H), 4.73 (s, 1 H), 4.00 (t, J = 6.5 Hz, 1 H), 3.62
(s, 3 H), 2.50 (q, J = 10 Hz, 1H), 1.73 (d, J = 5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ major: 177.9, 147.7, 110.6, 53.1, 52.5, 43.9, 36.5,
30.1, 23.3, 24.3, 20.6; HRMS (FAB+) calcd for C11H18O2 [M]+
182.1307, found 182.1310.
Methyl 2-Benzyl-1-methylcyclopentanecarboxylate (4e or 4f).
The compound was isolated as a mixture of diastereomers (52:48) in
97% yield (44 mg) from 0.2 mmol of 1e: 1H NMR (400 MHz,
CDCl3) δ major: 7.19−7.13 (m, 5H), 3.70 (s, 3H), 2.83−2.77 (m,
2H), 2.61−2.07 (m, 3H), 1.94−1.47 (m, 4H), 1.30 (s, 3H); minor:
7.19−7.13 (m, 5H), 3.58 (s, 3H), 2.61−2.07 (m, 5H), 1.94−1.47 (m,
4H), 1.17 (s, 3H); 13C NMR (125 MHz, CDCl3) δ major: 177.5,
141.6, 128.8, 128.2, 125.8, 53.6, 52.4, 51.3, 38.8, 37.4, 30.8, 22.5, 17.5;
minor: 178.5, 141.5, 128.8, 128.2, 125.7, 51.7, 51.2, 49.1, 37.3, 36.8,
30.0, 24.3, 21.9; IR (neat) 3026, 2926, 2871, 2855, 1725, 1603, 1496
cm−1; HRMS (FAB+) calcd for C15H21O2 [M + H]+ 233.1542, found
233.1555.
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on the energy surfaces of the radical 2i, particularly on that of its
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geometry has been optimized repeatedly with both the Gaussian03 and
the Gaussian09 codes, with varying results. The best agreement with
the experiment has been obtained by using the Gaussian09 code with
standard optimization procedure, so those numbers are given in Tables
1 and 2.
1946
dx.doi.org/10.1021/jo402499w | J. Org. Chem. 2014, 79, 1938−1946