Hydromethylation of Unactivated Olefins

Article abstract of DOI:10.1021/jacs.5b05144

A solution to the classic unsolved problem of olefin hydromethylation is presented. This highly chemoselective method can tolerate labile and reactive chemical functionalities and uses a simple set of reagents. An array of olefins, including mono-, di-, and trisubstituted olefins, are all smoothly hydromethylated. This mild protocol can be used to simplify the synthesis of a specific target or to directly "edit" complex natural products and other advanced materials. The method is also amenable to the simple installation of radioactive and stable labeled methyl groups.

Full text of DOI:10.1021/jacs.5b05144

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Communication
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Hydromethylation of Unactivated Olefins
Hai T. Dao,† Chao Li,†,§ Quentin Michaudel,†,§ Brad D. Maxwell,‡ and Phil S. Baran*,†
†Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
‡Discovery Chemistry Platforms-Radiochemistry, Bristol-Myers Squibb, Route 206 and Province Line Road, Princeton, New Jersey
08543, United States
S
* Supporting Information
ABSTRACT: A solution to the classic unsolved problem
of olefin hydromethylation is presented. This highly
chemoselective method can tolerate labile and reactive
chemical functionalities and uses a simple set of reagents.
An array of olefins, including mono-, di-, and trisubstituted
olefins, are all smoothly hydromethylated. This mild
protocol can be used to simplify the synthesis of a specific
target or to directly “edit” complex natural products and
other advanced materials. The method is also amenable to
the simple installation of radioactive and stable labeled
methyl groups.
he direct, chemoselective hydromethylation of unactivated
olefins is a classic unsolved problem of great importance
T
in organic chemistry. This is clearly illustrated in the context of
the total synthesis of 7-desmethyl-2-methoxycalamenene 2a
(Figure 1A).1a,b To be sure, three different indirect pathways
were engineered to accomplish the seemingly simple addition
of methane across olefin 1a. In the first approach, a Wacker/
Wittig sequence provided intermediate A in low yield. Although
the route via B gave an improvement in yield, a toxic mercury
reagent was required. Finally, the most frequently used strategy
for formal hydromethylation of olefins, employing a Simmons−
Smith cyclopropanation and a reductive C−C bond cleavage
(via C), gave an unsatisfactory yield.1b−d This Communication
reports a solution to this frequently encountered issue with the
invention of a mild, scalable, and catalytic olefin hydro-
methylation. This simple method can be used at both the early
and late stages of a synthesis, enabling access to uniquely
modified natural products, medicinally relevant molecules, and
even isotopically labeled structures that would be difficult or
impossible to access in any other way.
Figure 1. (A) Direct olefin hydromethylation, an unsolved problem in
organic synthesis. (B) Precedents for hydromethylation. (C) Reaction
blueprint with potential complications.
functionalizations benefit from inherently mild conditions
which tolerate a variety of unprotected functionality.7 Since
such reactions are thought to proceed via a nucleophilic radical
3 (Figure 1C), a variety of potential electrophilic methyl group
surrogates were evaluated without success (see Supporting
Information (SI)). In this context, the Kim group’s
demonstration that radicals could add to hydrazones in an
intramolecular context was particularly inspiring.8 In principle,
capture of 3 with hydrazone 5 would form alkyl hydrazide 4,
which can eliminate sulfinic acid and nitrogen to yield the net
hydromethylated adduct 2. The successful execution of this
plan would hinge on the ability to suppress byproducts
resulting from reduction,9 oxidation,3−5 dimerization, and
isomerization.10
Precedents for the direct hydromethylation of olefins exist
sporadically but are too substrate specific to be applicable in
medicinal and natural product synthesis (Figure 1B).2 For
example, Tilley described a conceptually appealing trans-
formation for hydromethylation using methane via an in situ-
formed methylscandium species.2a Only four unfunctionalized
alkenes were employed due to the pyrophoric properties and
the selectivity of the catalyst. In a different approach, Kambe
reported a single example of direct hydromethylation of styrene
employing a Cp2ZrCl2/nBuMgCl system, with methyl tosylate
as the methylating reagent.2b
Following the pioneering work of Mukaiyama,3 we and
others have invented a series of direct olefin functionalizations
using Co-,4 Mn-,4d,5 and Fe-based systems.3d,6 Mukaiyama-type
Received: May 18, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b05144
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Journal of the American Chemical Society
Communication
Reducing this design to practice required extensive
experimentation, the essence of which is summarized in
Table 1. Initial efforts to isolate formaldehyde hydrazone 5
any desired product (entries 9−11). These findings highlight
the unique properties of iron catalysts for the current C−C
bond-forming reaction. In contrast to prior studies,6e,f THF
proved superior to ethanol for the current transformation
(entry 12). Ultimately, addition of the same overall quantity of
reagents in two separate portions (separated by 15 h) proved to
be more effective (entry 13). Finally, with the use of trimethyl
borate as an additive, a catalytic reaction could be achieved
(entry 14, catalytic protocol).
Table 1. Effect of Reaction Parameters on the
Hydromethylation of 1b
The scope of olefins that can be hydromethylated is
illustrated in Table 2. Monosubstituted olefins bearing an
aromatic triflate and even a free phenol worked smoothly
(1c,d), as did a carbohydrate derivative (1e). 1,1-Disubstituted
olefins (1f−m) tend to give higher yields of the hydro-
methylated products (2f−m), with the exception of the
sterically hindered isopulegol derivative 1n. Cyclic structures
such as methylenepiperidine derivative 1o gave a gem-dimethyl
product in high yield, highlighting a new retrosynthetic
disconnection to gem-disubstituted systems.11 Trisubstituted
olefins 1p−r also delivered the desired methylated derivatives
2p−r in 41−61% yield. As Table 2 shows, the current
transformation can tolerate a wide variety of acid-labile, Lewis
basic, and reducible functional groups such as free alcohols,
phenols, azides, alkynes, aliphatic halides, triflates, aromatic
halides, and boronic esters.
Where the Fe-mediated hydromethylation really shines, and
is likely to find widespread application, is in the context of late-
stage diversification (Figure 2). For example, Apronal (1s), a
hypnotic and sedative drug, could be directly transformed into
hydromethylated derivative 2s in 44% yield. Complex natural
products such as 1t−v could be hydromethylated, forming 2t−
v in synthetically useful yields. A gram-scale transformation
employing rotenone (1t), an active component of an organic
insecticide known as derris, highlights the practicality of the
current methodology. Next, two notoriously unstable and
sensitive complex natural products were hydromethylated:
picrotoxinin12a (1u) and gibberellic acid12b,c (1v). Both of these
highly congested terpenes, bearing reactive functionalities such
as epoxides, free hydroxyl groups, carboxylic acids, strained
lactones, and even another olefin, were chemoselectively
hydromethylated (as verified by X-ray crystallography). One
would be hard pressed to access these structures in any other
way.
To highlight the step-economy of this newly developed C−C
bond-forming methodology, the synthesis of terpene derivative
2w, alkaloid derivative 2x, and norsesquiterpene 2a was
demonstrated (Figure 3). Previously, 2w was synthesized in
racemic form from crotonaldehyde in a four-step route.13 It can
now be synthesized in an enantiopure form from readily
available citronellol (1w) in 68% yield. Hydromethylated
quinine analogues such as 2x were previously accessed in a
labor-intensive four-step sequence14 but can now be accessed
directly in 32% yield. It is noteworthy that tertiary amine and
quinoline moieties are tolerated under the mild reaction
conditions. Lastly, the synthesis of 7-desmethyl-2-methoxy-
calamenene (2a) from the precursor 1a is a testament to the
simplicity of this approach in the context of natural product
synthesis. Indeed, the desired norsesquiterpene 2a was accessed
in 29% yield, making this synthesis superior in yield and step
count to all prior multi-step approaches (Figure 1A).1
yield (%)
b
b
b
entry
deviation from standard protocol
1b
2b
2b′
1
2
none
9
51
47
12
15
nBuSO2NHNH2 instead of
11
18
1
nOctSO2NHNH2
3
4
5
6
7
nDecSO2NHNH2 instead of
nOctSO2NHNH2
36
21
19
31
22
31
8
iPrSO2NHNH2 instead of
36
22
20
21
nOctSO2NHNH2
p-MeC6H4SO2NHNH2 instead of
27
2
nOctSO2NHNH2
p-MeOC6H4SO2NHNH2 instead of
nOctSO2NHNH2
p-BrC6H4SO2NHNH2 instead of
18
nOctSO2NHNH2
8
9
Fe(dibm)3 instead of Fe(acac)3
19
nd
18
nd
d
Fe2(ox)3/NaBH4 instead of Fe(acac)3/
0
PhSiH3
c
d
10
11
12
13
14
Co(II) and Co(III) instead of Fe(acac)3 nd
0
nd
nd
16
e
d
Mn(III) instead of Fe(acac)3
EtOH instead of THF
nd
0
0
35
f
g
g
reagents added in two portion
3
53
15
4
h
g
catalytic protocol
0
56 (51 )
a
b
c
Degassed and run under argon. According to GC analysis. Co(Sal)
(1 equiv) or Co(SaltBu,tBu) (1 equiv) or Co(acac)3 (2 equiv).
d
e
According to LC-MS. Mn(dpm)3 (2 equiv) or Jacobsen’s catalyst
(0.5 equiv). First portion: CH2O (3.0 equiv), OctSO2NHNH2 (2.5
f
n
equiv), Fe(acac)3 (1.0 equiv), PhSiH3 (2.0 equiv), MeOH (2.0 equiv),
g
h
THF, rt, 15 h. Second portion: 18 h. Isolated yields. This catalytic
protocol requires B(OMe)3, as without it, the reaction gives <30%
conversion. nd = not detected.
failed, presumably due to oligomerization. However, detection
by LC-MS suggested that in situ use of 5 was feasible. To
suppress the formation of oxidized byproducts, the reaction was
degassed and conducted under an inert atmosphere. Systematic
screening of reaction parameters led to the invention of a one-
pot protocol for the transformation of 1b to 2b. Thus, Fe-
mediated addition of 1b to in situ-formed hydrazone 5 yielded
hydrazide 4b in THF; a solvent switch to methanol and gentle
heating at 60 °C facilitated reductive C−N bond cleavage to
deliver 2b in good yield (entry 1).
Entries 2−7 summarize the search for an optimal R-
substituent on the hydrazone “donor” (5), eventually identified
as the n-octyl group. The use of a more sterically hindered
catalyst (Fe(dibm)3, entry 8) led to a slower reaction, while
replacement of iron with other metal complexes did not yield
Another striking use of the current methodology is in the
context of isotopic labeling. In theory, since formaldehyde is
readily available in a myriad of radioactive and stable labeled
B
DOI: 10.1021/jacs.5b05144
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Journal of the American Chemical Society
Communication
Table 2. Substrate Scope of Hydromethylation Reaction
a
n
Standard protocol: first portion, CH2O (3.0 equiv), OctSO2NHNH2 (2.5 equiv), 4 h; Fe(acac)3 (1.0 equiv), MeOH (0−2 equiv), PhSiH3 (2.0
b
n
equiv), THF, rt, 8−15 h; second portion, 8−15 h. Catalytic protocol: CH2O (6.0 equiv), OctSO2NHNH2 (5.0 equiv), 4 h; Fe(acac)3 (0.3−0.5
equiv), B(OMe)3 (2−5 equiv), PhSiH3 (2.0 equiv), THF, rt, 40 h. Isolated yields. Isolated yields, as a mixture with 2l′, ratio 2l:2l′ > 15:1. Isolated
yields, as a mixture with 2m′, ratio 2m:2m′ > 6:1.
c
d
e
Figure 3. Direct hydromethylation as a step-economic method.
Figure 2. Diversification of complex molecules.
radioactive methyl group (14CH3) was installed to rotenone
forms, it can be used to prepare methyl groups with many
permutations of 14CHn, 13CHn, 12CDn, 13CDn, and 12CTn. As a
proof of concept, L-Fmoc-allylglycine-OMe (1y) was converted
into L-Fmoc-leucine-OMe (CH3) and stable labeled derivatives
containing CDH2 (2y-d1), CD2H (2y-d2), and CD3 (2y-d3) in
>40% isolated yield without erosion of enantiopurity (Figure
4). Deuterium incorporation was >99% in the case of 2y-d2 and
>75% in the other two cases; presumably this is due to
incomplete deuteration of the intermediate alkylhydrazide. The
divergent synthesis of leucine derivatives shown here may find
use in the stereo-array isotope labeling technique15 and
carbon−deuterium probes in vibrational spectroscopy.16 In an
application in the synthesis of labeled drugs, (R,S)-Fmoc-
pregabalin-OtBu-d2 (2z) was smoothly labeled from simple
precursor 1z. As a final showcase of the utility of this method, a
(1t) using commercially available [14C]formaldehyde solution.
Currently, this method has clearly defined limitations. For
example, styrenes gave poor yields owing to the homodimeriza-
tion byproducts. In the case of sterically hindered substrates
(e.g., 1a, 1n, 1u, 1v, and 1x), lower yields of the desired
products together with an increased amount of reduced
byproducts were obtained. Procedurally, this reaction requires
more experimental care than our previously reported Fe-
mediated reactions6e,f (see troubleshooting section in SI), and
separation of the desired hydromethylated product from the
reduced byproduct can sometimes be difficult.
A synthetically useful procedure for the formal addition of
methane across a π-system has remained elusive and was
heretofore only possible using multi-step sequences. This
chemoselective, catalytic, one-pot method provides a solution
C
DOI: 10.1021/jacs.5b05144
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Communication
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and analytical data (1H and 13C
NMR, MS) for all new compounds. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/jacs.5b05144.
AUTHOR INFORMATION
Corresponding Author
*pbaran@scripps.edu
■
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Author Contributions
§C.L. and Q.M. contributed equally to this paper.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this work was provided by NIH/NIGMS
(GM-097444), Fulbright S&T Awards (predoctoral fellowship
to H.T.D.), and China Scholarship Council (postdoctoral
fellowship to C.L.). The authors thank A. L. Rheingold and C.
E. Moore for X-ray crystallographic analysis, Dr. D.-H. Huang,
Dr. L. Pasternack for assistance with NMR spectroscopy, Mr. J.
T. Edwards for suggestion for the use of borate additives, and
Dr. K.-J. Xiao and Dr. A. Okano for assistance with chiral and
reverse phase HPLC.
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