Radical Isomerization and Cycloisomerization Initiated by H? Transfer

Article abstract of DOI:10.1021/jacs.6b03509

Under H₂ pressure, Co^II(dmgBF₂)₂L₂ (L = H₂O, THF) generates a low concentration of an H? donor. Transfer of the H? onto an olefin gives a radical that can either (1) transfer an H? back to the metal, generating an isomerized olefin, or (2) add intramolecularly to a double bond, generating a cyclized radical. Transfer of an H? back to the metal from the cyclized radical results in a cycloisomerization. Both outcomes are favored by the low concentration of the cobalt H? donor, whereas hydrogenation and cyclohydrogenation are more likely with other catalysts (when the concentration of the H? donor is high).

Full text of DOI:10.1021/jacs.6b03509

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Article
Radical Isomerization and Cycloisomerization Initiated by H# Transfer
Gang Li, Jonathan L. Kuo, Arthur Han, Janine M. Abuyuan,
Lily C. Young, Jack R. Norton, and Joshua H. Palmer
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b03509 • Publication Date (Web): 11 May 2016
Downloaded from http://pubs.acs.org on May 13, 2016
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Radical Isomerization and Cycloisomerization Initiated by H• Transfer
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Gang Li,§,† Jonathan L. Kuo,§,† Arthur Han,† Janine M. Abuyuan,‡ Lily C. Young,† Jack R.
Norton,*,† and Joshua H. Palmer†
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†Department of Chemistry, Columbia University, 3000 Broadway, New York, New York 10027
‡Department of Chemistry, Barnard College, 3009 Broadway, New York, New York 10027
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Abstract
Under H2 pressure CoII(dmgBF2)2L2 (L = H2O, THF) generates a low concentration of an
H• donor. Transfer of the H• onto an olefin gives a radical that can either (1) transfer an H• back
to the metal, generating an isomerized olefin, or (2) add intramolecularly to a double bond,
generating a cyclized radical. Transfer of an H• back to the metal from the cyclized radical
results in a cycloisomerization. Both outcomes are favored by the low concentration of the cobalt
H• donor, whereas hydrogenation and cyclohydrogenation are more likely with other catalysts
(when the concentration of the H• donor is high).
Introduction
The use of transitionꢀmetal hydrides to isomerize olefins has been known for many years.
The bestꢀknown early example, with HRh(CO)3(PPh3)3, was published by Wilkinson in 1970.1
Generally, these reactions are thought to occur by (1) insertion of the olefin into the M–H bond,
and (2) βꢀhydrogen elimination in the opposite direction along the carbon chain. Many of the
hydrideꢀcatalyzed olefin isomerizations discussed in a recent review2 occur by this mechanism.3,4
A plausible alternative mechanism for isomerization begins with hydrogen atom transfer,
or HAT.5 The rates of H• transfer to alkenes6 and alkynes7 from CpCr(CO)3H have been reported,
giving the relative rates shown in Scheme 1, and enabling us to predict which radicals will be
formed. Abstraction of an H• from a different carbon would result in isomerization.
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Scheme 1. Relative Rate of H• Transfer to Various Olefins from CpCr(CO)3H
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We have reported that the isomerization in equation 1 can be catalyzed in low yield by
CpCr(CO)3H under H2,8 and in much higher yield by a cobaloxime like 1a under H2.9 The Shenvi
group has reported that the cobalt salen complex 2, when treated with PhSiH3, can effect
isomerizations (e.g., eq 2),10 also apparently via HAT from a cobaltꢀbased H• donor. In both
cases the isomerization goes from a 1ꢀsubstituted or 1,1ꢀdisubstituted double bond to only the
first internal position, and does not proceed to the most stable alkene.10, 11
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With appropriate diene substrates the radical formed by HAT (e.g., 5R) can cyclize.6b, 7ꢀ8,
10 With traditional H• donors (such as SnBu3H) the result is a reductive cyclization, or
cyclohydrogenation. Alternatively, the removal of a hydrogen atom from the cyclized radical
will give a cycloisomerization.12 We first became aware of this possibility when we observed that
some cyclization substrates — those with sterically accessible methyl groups — lost an H• with a
catalyst that normally effected cyclohydrogenation (CpCr(CO)3H in eq 313 or HV(CO)4dppe in eq
48b). The Shenvi group has reported additional examples with the cobaltꢀcontaining 2 (eq 5), as
well as the retrocycloisomerization of substrates that contain strained rings.10
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H
Ph
Me
Ph
Me
Ph
Ph
•
CpCr(CO)3H (7 mol%)
H
(3)
H
H
3 atm H2, C6H6
50 °C, 14h
MeO2C
MeO2C
•
5R
H
MeO2C
MeO2C
5
6R
6, 74%
H
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CH3
CH3
•
H3C
H
H3C
H
H3C
HV(CO)4dppe (2 eq)
(4)
(5)
H
•
C6H6
50 °C, 6h
MeO2C
MeO2C
MeO2C
MeO2C
EtO2C CO2Et
EtO2C CO2Et
EtO2C CO2Et
EtO2C CO2Et
2 (3 mol%)
•
Me
Me
Me
PhSiH3 (6 mol%)
C6H6, 22 °C
Me
Me
Me
Me
•
Me
Me
H
Me
H
H
H
94%
We also observed a cycloisomerization in one cobaloximeꢀcatalyzed case (eq 9, below),9
and became interested in the factors determining the outcome of such reactions. We now offer a
detailed account of the catalysis of the isomerization of olefins, and of the cycloisomerization of
dienes, by Co(dmgBF2)2(THF)2 (1b) under H2.14
Experimental
All manipulations were performed under an argon atmosphere using standard Schlenk or
inert atmosphere box techniques. NMR spectra were taken on either a Bruker 300, 400, or 500
MHz spectrometer. IR spectra were taken with a PerkinꢀElmer Spectrum 2000 FTꢀIR
spectrometer. Crystal data, data collection and refinement parameters are summarized in the SI
(Table S1). The structures were solved using direct methods and standard difference map
techniques, and were refined by full matrix least squares procedures on F2 with SHELXTL
(Version 6.1).15 Benzene and THF were distilled from Na or K/benzophenone ketyl. Benzeneꢀd6
(Cambridge Isotope Laboratories) was dried by distillation from K/benzophenone ketyl and then
deoxygenated by three freezeꢀpumpꢀthaw cycles, then stored over 3 Å molecular sieves. All
liquids were dried by distillation from CaH2 and then deoxygenated by three freezeꢀpumpꢀthaw
cycles and stored under an argon atmosphere.
Procedure for Cyclizations. Caution! All reactions under gas pressure should be properly
shielded! A solution of cobaloxime (1) (7 mol %) and benzene were prepared in a FischerꢀPorter
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reactor, and the substrate was added. The vessel was sealed and then pressurized to 6 atm, and
then placed in an oil bath at 50 C. After stirring for the amount of time indicated in the reaction
conditions, the reaction was allowed to return to room temperature, and the H2 pressure was
vented. The crude reaction mixture was run through a plug of silica, concentrated inꢀvacuo, then
subjected to column chromatography to afford the reaction products. Spectral details of all the
reaction products can be found in the supporting information.
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Results & Discussion
Isomerization Reactions. Kinetic analysis of the rate at which various Co(dmgBF2)2L2
activate H2 in benzene has shown that k1 (equation 5) increases by an order of magnitude between
L = H2O (1a) and L = THF (1b).16 The THF complex 1b should thus be more effective than 1a at
catalyzing isomerizations under H2, so 1b has been used in examining the scope of the
isomerization reaction. Even with 1b, however, these reactions require a day or more under 6
atm of H2 at 50 °C. (Because the resting state of the catalyst is Co(II),9 the concentration of the
H• donor17 is low.14)
k1
C6H6
2 Co(dmgBF2)2L2
2 Co(dmgBF2)2(L)H
+
H2
+
2 L
(6)
By analogy with the results in Scheme 1 we expected that a terminal or 1,1ꢀdisubstituted
olefin — with radicalꢀstabilizing substituents — would accept H• effectively. Thus transfer to the
methylene carbon in 7 results in its isomerization to the enol ether 8 (entry 1 in Table 1). Such
isomerizations18 have previously been achieved with strong bases (e.g. nꢀBuLi),19 or with Lewis
acidic transitionꢀmetal catalysts (e.g., (Ph3P)3RhCl20 or Ir(PCy3)3+ 21), but a radicalꢀbased
methodology should offer greater scope and functional group tolerance.
Table 1. Coꢀcatalyzed Isomerization Reactions
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yielda
75%
entry
1
substrate
product
CH3
OMe
OH
OMe
7
8
O
O
2
3
78%
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9
10
OMe
OH
O
O
O
Me
>95%
OMe
11
12
MeO
Me
CH3
4
5
> 95%
74%
OTBDPS
OTBDPS
CH3
N
N
O
O
6
> 95%
OMe
OMe
Cl
Cl
CH3
O
O
Ph
Ph
7
8
52%
86:14 E:Z
O
O
O
O
O
CH3
O
O
Ph
Ph
Ph
83%
75:25 E:Z
O
Ph
S
9
87%
77:23 E:Z
CH3
OH
O
S
10
O
O
65%
OMe
H3C
OMe
a
1b
Reaction conditions:
(7 mol%), 6 atm H2, C6H6 at 50 °C for 1.5 d.
Similarly, a phenylꢀsubstituted allylic alcohol 9 is isomerized to an aldehyde 10 (entry 2),
presumably via an enol intermediate. 14, 22 We expected a similar result with the carbomethoxyꢀ
substituted allyl alcohol 11 (entry 3), but were surprised to isolate a dienol ether 12 instead
(which was identified by xꢀray crystallography, details in the SI). Presumably, 11 first results in
the generation of 13, which is in equilibrium with its aldehyde tautomer 14 (see eq 7). We
prepared and isolated, by a reported method,23 an equilibrium mixture of 13 and 14, and subjected
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the mixture to the conditions in Table 1. However, we did not observe the formation of 12,
suggesting that the latter is formed from the reaction of 13 or 14 with 12 under the influence of
the cobalt catalyst 1b. A general method for the synthesis of dienol ethers such as 12 has been
reported,24 and several workers have reported dienol ethers as byproducts, though they are
probably formed by a different mechanism.25
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With unconjugated dienes (entries 4 and 7) we observed the selectivity predicted by the
data in Scheme 1:6a the 1,1ꢀdisubstituted double bond, with a phenyl substituent, is isomerized in
preference to the terminal double bond. In entry 4 the result is a skipped diene in greater than 95%
yield, while entry 7 gives an enol carbonate. These entries illustrate the mildness of our reaction
conditions, as both of the functionalities that result are quite reactive. Our results complement the
recent HAT isomerizations by Shenvi and coworkers: at room temperature their Co(salen)
system isomerizes 1ꢀdecene (a model for the terminal double bonds in entries 4 and 7),10 implying
that the H• donor in their system is more reactive.
Donor substrates often inhibit metalꢀcatalyzed isomerizations by preventing olefin
coordination.26 However, the cobaloxime/H2 system tolerates free alcohols (entries 2, 3, 10),
ketones (entries 8, 9), carbonates (entry 7), and heterocycles (entries 5, 10); this tolerance of
Lewis bases is consistent with the fact that the HAT reaction does not require coordination of the
olefin.27 A pyridine can also replace a phenyl (entry 5) as the radicalꢀstabilizing substituent on the
olefin substrate. The isomerization reaction tolerates an aryl chloride (entry 6), indicating that a
chlorine atom is not easily abstracted by CoII(dmgBF2)2L.
Scheme 2 shows the alternatives available to a radical 15R after it has been formed by H•
transfer to a substrate 15. For the substrates in Table 1 the alternatives to isomerization (kiso[M•])
are in principle hydrogenation (khyd[M–H]) and back transfer (ktr[M•]). However, we have not
observed hydrogenation byproducts in any of the cases in Table 1, implying that khyd[M–H] does
not compete effectively with kiso[M•] when 1b is used as a catalyst.
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Scheme 2. Alternatives Available to a Radical Formed by H• Transfer to an Olefin
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8
R1
R2
+ M H
isomerization
H
k
iso1[M•]
R2
MeO2C
9
R1
cycloisomerization
iso2[M•]
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+ M H
R1
R2
k
R2
R1
R2
H
•
R1
H
kH[M H]
ktr[M•]
H
cyclization
MeO2C
kcyc
•
H
H
R2
MeO2C
MeO2C
MeO2C
R1
15
15R
16R
R2
H
cyclohydrogenation
+ M•
khyd2[M H]
R1
H
H
MeO2C
hydrogenation
khyd1[M H]
+ M•
H
MeO2C
With a stable hydride as an H• donor5bꢀe, 6b, 7, 28 the second transfer is faster than the first.
With CpCr(CO)3H and αꢀcyclopropylstyrene, for example, Bullock has measured the rate
constant kH as 3.4 × 10–3 Mꢀ1 sꢀ1 at and has estimated the rate constant khyd1 as 2.3 × 107 Mꢀ1 sꢀ1
(both at 22 °C, Eq 8).27 In the cases in Table 1, however, the concentration of the cobalt H• donor
is so low that the rate of the second transfer is negligible.
5-Exo Cyclizations, and the Resulting Cycloisomerizations. If the radical generated
by H• transfer has an appropriate internal double bond like 15R, it can cyclize to a radical like
16R. That radical, like 15R, can accept another H• (khyd2[M–H], cyclohydrogenation) or have an
H• abstracted (kiso2[M•], cycloisomerization). Our earlier work, with CpCr(CO)3H and
HV(CO)4dppe, largely gave cyclohydrogenation, although eqs 3 and 4 show exceptions. Such
cycloisomerization reactions, which neither add nor subtract atoms but merely rearrange those in
the starting material, offer excellent atom economy.29
Earlier we had also (in view of the ability of acyl substituents to stabilize radicals)30
replaced the acrylate in eq 3 with an enone.13,31 With CpCr(CO)3H, 17R accepted a second H•
before it cyclized; however with 1a we obtained 50% cycloisomerization. We concluded that the
cobalt catalyst not only limited the hydrogenation of 17R, but abstracted an H• from the cyclized
radical 18R (eq 10).
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Given the effectiveness of 1b at activating H2 (see above), the reaction in eq 9 should be
faster with 1b as catalyst rather than 1a. Indeed, catalyst 1b gives not only an increase in rate but
an improvement in yield (entry 1 in Table 2). Similar results are obtained without a methyl
substituent on the α carbon (entry 2), though the double bond now moves to a position within the
ring. Acrylate esters give even better yields (entries 3–8), slightly higher when the substituents
on C5 and C6 are trans (entry 3, 4) (a pattern we observed earlier with CpCr(CO)3H).13 Moderate
yields are obtained with the indole derivative in entry 9 and the substituted benzene in entry 10, in
both cases presumably because the planarity of the aromatic system makes cyclization more
challenging.8b
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Table 2. Cycloisomerization Reactions
5
6
7
8
yielda
61%
entry
substrate
product
H2C CH3
O
O
1
O
CH3
9
Ph
Ph
Ph
Ph
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CH3
2
3
57%
O
H3C CO2Me
Ph
>95%
CO2Me
Ph
H3C
CO2Me
Ph
CO2Me
4
5
92%
88%
Ph
CH3
CO2Me
CO2Me
CH3
Ph 66:34 d.r.
Ph
CH3
CO2Me
CO2Me
6
95%
CH3
Ph
Ph
54:46 d.r.
CO2Me
Ph
7
8
>95%
90%
CO2Me
O
Ph
O
H3C CO2Me
HO
HO
CO2Me
Ph
Ph
Ph
CO2Et
Ph
9
N
67%
80%
N
CO2Et
CH3
10
Ph
Ph
Me
Ph
Ph
11
> 95%
CH3
MeO2C
MeO2C
MeO2C
MeO2C
CO2Me
CO2Me
62:38 d.r.
a Reaction conditions: 1b (7 mol%), 6 atm H2, C6H6 at 50 °C for 1.5 d.
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As in the isomerization reactions in Table 1, our cobalt cycloisomerization catalyst 1b
tolerates an unprotected hydroxyl substituent (entry 8), or an oxygen in the backbone (entry 7).
The latter is known to increase the rate of cyclization reactions,32 although 1b does not require
this increase to produce good yields. In contrast, the PhSiH3/Co(salen) system seems to require
heteroatom acceleration or the ThorpeꢀIngold effect.10 We expect the broad functional group
tolerance demonstrated in Table 1 to translate into functional group tolerance for
10
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cycloisomerization — if the corresponding cyclizations are fast enough.
After any of these substrates cyclizes to a fiveꢀmembered ring, the radical center moves
to C6. A hydrogen atom can be abstracted not only from any suitable substituent on C6 (entries 5
and 6) but also (when there is no suitable substituent on C6) from C5 (entries 1, 3, 4, 7, and 8–10),
as the C–H bonds on that carbon have been weakened by the adjoining radical center.33
Cycloisomerizations of the former type have been reported by Shenvi and coꢀworkers (see eq 4
above),10 but cycloisomerizations of the latter type have not been reported for the
PhSiH3/Co(salen) system.
Slower Cyclizations. As Scheme 2 and the resulting eq 10 show, isomerization and
hydrogenation can compete with cyclization and decrease the yield of cyclized product. 5ꢀExo
cyclizations are straightforward, because their kcyc is large.34 Any change that decreases kcyc will
permit the radical to react in other ways. For example, 6ꢀendo and 7ꢀendo cyclizations are
generally slower than 5ꢀexo cyclizations.35 (The 5ꢀexo cyclization36 of the 5ꢀhexenyl radical is
about 50 times faster than the 6ꢀendo one.)35a, 37
We have attempted the cyclization of 20, in part because its structure eliminates the
possibility of isomerization. Even with the Co catalyst 1b, however, hydrogenation to 21 is
quantitative after 4 days.
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In other cases we can avoid both isomerization and hydrogenation. As with 19, the
structure of 21 makes isomerization impossible, and no hydrogenation is observed after several
days. However, instead of the cyclized 22, we isolate a good yield of the dimer 23 (Scheme 3).35b,
38
Presumably the initial radical 22R adds to another equivalent of 21 more rapidly than it
cyclizes, and abstraction of H• from 23R produces 23. Diluting the reaction tenfold suppresses
the formation of 23, but we recover only starting material. Apparently kcyc for a 7ꢀendo
cyclization is simply too slow.37, 39
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Scheme 3. Potential Reaction Pathways for 21
Transfer of H• Back to the Catalyst. It is apparent from Scheme 2 that transfer of H•
back to M• (ktr[M•]) can compete with isomerization, cyclization, and hydrogenation. The direct
measurement of ktr is not practical, given the poor solubility of 1b and the reactivity of the
organic radical. Some information is available if we carry out the reaction under D2. For
example, deuterium is incorporated into both the a and the b positions when reaction 14 is run
under a D2 atmosphere at high dilution; H• transfer must be occurring, but reversibly (eq 12).
In reaction 25 there is a net (and quantitative) isomerization of 24 to 25. Under D2 there
is H/D exchange at the expected position c, demonstrating reversible H• transfer to the methylene
of the acrylate 24. There is also some H/D exchange at the more congested position d, which
implies that after its initial formation, 25 can reversibly accept D• (regenerating 24R).
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Eq 14 achieves a cycloisomerization in good yield. Under D2 there is again H/D
exchange at the g position (the acrylate double bond), but more H/D exchange occurs at positions
e and f of the terminal methylene in the product 27. These results imply that the abstraction of H•
from 27R is fast and reversible.
Conclusion
Both CpCr(CO)3H and Co(dmgBF2)2(THF)2 are effective H• donor systems under H2, i.e.
both can promote the formation of 28R from 28. However, they take 28R in different directions.
With CpCr(CO)3H, [MꢀH] is relatively high and the formation of 29 will prevail. With
Co(dmgBF2)2L2 (1), [M•] dominates and the formation of 30 is favored. Thus we can select the
fate of radicals such as 28R by the selection of catalyst.
The choice between the Cr and the Co catalysts also determines the mode of termination
after cyclization of the initial radical. With the substrate 31, for example, CpCr(CO)3H maintains
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a relatively high [M–H] and cyclohydrogenation will prevail. With Co(dmgBF2)2L2 (1), on the
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other hand, [M•] dominates and cycloisomerization will result (Scheme 4).
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Scheme 4. Catalytic Cycle for Cycloisomerizations with 1
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Associated Content
Starting material preparation, experimental procedures for cyclizations, characterization data 1H
and 13C NMR data, XꢀRay data collection.
Author Information
Corresponding Author:
jrn11@columbia.edu
Author Contributions:
§ G.L. and J.L.K Contributed Equally
Acknowledgements
This material was supported by the National Science Foundation under Grant No. CHEꢀ1401049
(IUPAC Novel Molecular and Supramolecular Theory and Synthesis Approaches for Sustainable
Catalysis). J.L.K. acknowledges the National Science Foundation Graduate Research Fellowship
Program (DGEꢀ11ꢀ44155). J.M.A. acknowledges the Con Edison Summer Internship in Science
through Barnard College for financial support. The National Science Foundation (CHEꢀ0619638)
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is thanked for the acquisition of an xꢀray diffractometer. The authors are grateful to Scott A.
Snyder, Andreas Gansäuer, and John Hartung for helpful discussions.
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