Site-Specific Alkene Hydromethylation via Protonolysis of Titanacyclobutanes

Article abstract of DOI:10.1002/anie.202103278

Methyl groups are ubiquitous in biologically active molecules. Thus, new tactics to introduce this alkyl fragment into polyfunctional structures are of significant interest. With this goal in mind, a direct method for the Markovnikov hydromethylation of alkenes is reported. This method exploits the degenerate metathesis reaction between the titanium methylidene unveiled from Cp₂Ti(μ-Cl)(μ-CH₂)AlMe₂ (Tebbe's reagent) and unactivated alkenes. Protonolysis of the resulting titanacyclobutanes in situ effects hydromethylation in a chemo-, regio-, and site-selective manner. The broad utility of this method is demonstrated across a series of mono- and di-substituted alkenes containing pendant alcohols, ethers, amides, carbamates, and basic amines.

Full text of DOI:10.1002/anie.202103278

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Accepted Article
Title: Site-Specific Alkene Hydromethylation via Protonolysis of
Titanacyclobutanes
Authors: James A. Law, Noah M. Bartfield, and James Frederich
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10.1002/anie.202103278
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COMMUNICATION
Site-Specific Alkene Hydromethylation via Protonolysis of
Titanacyclobutanes
James A. Law, Noah M. Bartfield and James H. Frederich*
[a]
Prof. Dr. J. H. Frederich
Department of Chemistry and Biochemistry
Florida State University
95 Cheiftan Way, Tallahassee, FL 32306, United States
E-mail: jfrederich@fsu.edu
Supporting information for this article is given via a link at the end of the document.
Abstract: Methyl groups are ubiquitous in biologically active
molecules. Thus, new tactics to introduce this alkyl fragment into
polyfunctional structures are of significant interest. With this goal
in mind, a direct method for the Markovnikov hydromethylation of
alkenes is reported. This method exploits the degenerate
metathesis reaction between the titanium methylidene unveiled
from Cp2Ti(µ-Cl)(µ-CH2)AlMe2 (Tebbe’s reagent) and unactivated
alkenes. Protonolysis of the resulting titanacyclobutanes in situ
effects hydromethylation in a chemo-, regio-, and site-selective
manner. The broad utility of this method is demonstrated across
a series of mono- and di-substituted alkenes containing pendant
alcohols, ethers, amides, carbamates and basic amines.
" indirect approach: reductive C–C bond cleavage
Me
1. [Zn]CH2I
2. H2, [MLn]
Me
cyclopropanation
hydrogenation
" state-of-the-art: metal-catalyzed hydrogen atom transfer (MHAT)
N
SO2R
Me
ii.
N
H
H2C
i. Fe(acac)
PhSiH3
H
H
iii. MeOH, Δ
(–N2)
A
" this work: protonolysis of titanacyclobutanes
Site-specific methylation is a valuable strategy to optimize the
pharmacology of bioactive small molecules.[1] This ‘magic methyl’
effect has inspired new strategies for selective C–H bond
methylation that facilitate the late-stage diversification of complex
structures.[2,3] The addition of methane across a C–C p-system
provides an appealing and complementary approach to small-
molecule methylation. Nevertheless, despite advances in catalytic
alkene hydrofunctionalization,[4] there are few direct methods for
Cp
Me
Cp
Cp
H—A
Ti
Ti
H
+
H2C
Cp
B (via 1)
C
inspiration –
Cl
Me
(Me)2Al
Ti(Cp)2
8
7
regioselective hydromethylation.[5–7]
A
procedure involving
(1, 1.5 equiv)
Me
Me
O
O
cyclopropanation and reductive C–C bond cleavage provides an
THF, 0 oC, 1 h
indirect approach to this problem (Figure 1).[8] In contrast, the
Me
Me
68%
H
H
Baran Group developed
a more direct, branch-selective
Me
Me
HO
HO
hydromethylation protocol using Fe-mediated hydrogen-atom
transfer.[9,10] Herein, we describe the utility of Cp2Ti(µ-Cl)(µ-
CH2)AlMe2 (1) as a hydromethylation reagent.[11] This method
facilitates site-specific incorporation of methyl substituents into
polyfunctional structures and circumvents several of the intrinsic
limitations of existing hydromethylation tactics.
Our interest in hydromethylation strategies emerged from a
program to synthesize fusicoccane diterpenes.[12] An early route
intercepted structure 2, from which the regioselective addition of
methane to the C7–C8 alkene became an attractive option to
install the C7 methyl group of this terpene family. In practice, the
poor reactivity profile of 2 made this task challenging. For example,
exposure of 2, or protected variants, to combinations of
electrophilic metals (e.g. Pd,[13] Fe,[14] Cu[15]) and nucleophilic
methyl surrogates (e.g. ZnMe2) returned only starting material.
Cyclopropanation was also intractable, requiring 10 equiv of
(TFA)ZnCH2I to achieve modest conversion.[16] Conversely, the
Mukaiyama-type hydromethylation reported by Baran yielded only
traces of target structure 3 alongside significant quantities of the
corresponding net hydrogenation product arising from competitive
reduction of radical species A.[17]
3 [X-Ray]
d.r. > 25:1, C7:C8 > 20:1
Figure 1. Regioselective hydromethylation of unactivated alkenes explored in
the context of structure 2.
2
degenerate metathesis reaction with unactivated alkenes.[20] In
select cases, the resultant titanacyclobutanes (i.e. C) have been
isolated and reacted with acid to give formal hydromethylation
products.[20] However, these examples are largely constrained to
simple hydrocarbons lacking other functional groups.[21,22] Thus,
with some experimentation, we were pleased to find that the
reaction of 1.5 equiv of 1 with 2 afforded 3[23] in 68% yield after
addition of SiO2 to the reaction.[24] The enhanced reactivity and
regioselectivity (C7:C8 = 21:1) achieved with reagent 1 in this
complex setting compelled us to explore further. Our efforts to
transform this chemistry into a general method for alkene
hydromethylation are summarized below.
Our study began with a detailed investigation of reaction
conditions (Table 1). Reaction parameters were explored using
piperidine 4, which reacted with a solution of 1 (0.3–0.4 M in
PhMe)[25] and DMAP at 0 °C.[19c] After 6 h, addition of HCl
furnished an inseparable mixture of net Markovnikov
hydromethylation product 5 (16% conversion) and 4 (entry 1). We
observed no reaction in the absence of a Lewis base (entry 2). In
contrast, the reaction was improved using THF as the Lewis base
In search of a solution, we revisited the pioneering work of
Tebbe[18] and Grubbs[19] concerning reagent 1, which serves as a
progenitor to titanium methylidene B. While best known as an
intermediate for carbonyl methylenation, B also participates in a
1
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10.1002/anie.202103278
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COMMUNICATION
Table 1. Summary of Reaction Optimization[a–c]
warming the reaction for 1 h before addition of HCl. This analysis
revealed significant cycloreversion to 4 after 1 h at 35 °C (50% by
1H NMR spectroscopy).[29] Conversely, 7 persisted for 10 h at 0
°C when precautions were taken to exclude air. The introduction
of oxygen (1 atm) resulted in the rapid formation of byproducts,
the most significant being aldehyde 8. However, when handled as
described, 7 functions as a useful 1,3-dianion equivalent. This
feature was showcased by reaction of DCl with 7 at 0 °C to furnish
isotopically labeled 5-d2 in 90% yield and ≥90% deuterium
incorporation.
standard
1 (1.2 equiv)
THF [0.1 M]
0 oC, 1 h
N
Me
then:
aq. HCl
Ts
H
4
6
0 oC, 6 h
N
alternative
Ts
O
1 (3 equiv)
5
[94% from 4]
[90% from 6]
N
THF [0.1 M]
0 oC, 3 h
Ts
As shown in Scheme 2, the regioselectivity of this method was
highlighted using a-olefins (9). In principle, both branched (b) and
Cp
Me
Entry
Deviation from Standard Protocol
Time (h)
% Yield 5
Ti
Me
H
Cp
1
2
3
4
5
6
7
PhMe, 1 equiv DMAP
PhMe
6
6
2
1
1
1
6
16[d]
0
1
standard
titanacycle I
branched (b)
alkane 10
then: TFA
–78 oC → rt
H
Cp
alkene 9
PhMe/THF (2:1)
none
80
Ti
Me
H
Cp
linear (l)
alkane 10
94
titanacycle II
TFA as proton source[e]
none, gram-scale
commercial solution of 1[f]
92
MeO
MeO
89
Ph
70[d]
O
N
Bn
[a] Yields are based on isolated 5. [b] Reactions were carried out on 0.2 mmol
scale. [c] Reagent 1 was prepared directly before use.[25] [d] Reflects conversion
of 4 to 5 as judged by 1H NMR spectra of the unpurified reaction mixture. [e]
The reaction was treated with TFA at –78 °C and warm to rt. [f] Commercial 1
was 0.52 M (in PhMe) as received.
10a: 72%
b:l ≥ 25:1
10b: 84%
b:l = 3:1
b:l = 6:1 [3 h]
10c: 52%
b:l ≥ 25:1
10d: 78%
b:l = 9:1
b:l ≥ 25:1 [6 h]
10e: 86%
b:l = 5:1
b:l ≥ 25:1 [3 h]
Temperature Profile for Substrate 9e [standard protocol, 3 h]
(entry 3) and the best results (94% yield) were obtained using
THF as the solvent (entry 4). We found that HCl could be replaced
by TFA without impacting reaction efficiency (entry 5). Moreover,
the reaction was executed on gram-scale to give 5 in 89% yield
(entry 6). Importantly, commercial solutions of 1 (0.5 M in PhMe)
did not give comparable results (entry 7). The concentration of 1
was accurate; however, commercial 1 was darker than solutions
of 1 freshly prepared from Cp2TiCl2 and AlMe3.[26] The same
problem was encountered with prepared solutions of 1 after ~120
h, suggesting formation of impurities upon storage.[27] With this
practical issue noted, we found that ketone 6 was converted to 5
in 90% yield with 3 equiv of 1 using otherwise identical conditions.
As such, this method also allows for the direct geminal
dimethylation of ketones.[28]
+
100
80
60
40
20
0
20
15
10
5
optimal
temperature range
0
0
10
10
20
20
30
30
40
40
50
50
60
-40 -30 -20 -10
-40 -30 -20 -10
0
-50
Temperature (oC)
A series of control reactions shed light on the properties of
titanacyclobutane 7 formed by the reaction of 1 and 4 (Scheme 1).
Scheme 2. Regioselective Hydomethylation of a-olefins.
linear (l) hydromethylation isomers of 10 are accessible via
protonolysis of titanacycles I and II, respectively. However, using
the standard protocol, 4-phenyl-1-butene (9a) gave branched
alkane 10a (72% yield, >25:1 b/l), indicating selective generation
of the primary alkyl titanacycle I. By comparison, pyridine
congener 9b afforded 10b in 71% yield, but with reduced
regioselectivity (3:1 b/l). In this case, the secondary alkyl
titanacycle II is stabilized by coordination to the pendant nitrogen
atom via a six-membered chelate. Increasing the reaction time to
3 h before the addition of acid improved the branched selectivity
(10b, 3:1 ® 6:1 b/l), suggesting that intermediates I and II
equilibrate under the reaction conditions. A directing effect was
not observed using homoallylic ether 9c, as shown by the
regioselective formation of 10c after 1 h (52% yield, >25:1 b/l). In
contrast, modest branched selectivity was observed after 1 h with
allyl arene derivatives 9d and 9e. As expected, the regioselectivity
in both cases was enhanced to >25:1 by extending the reaction
time. This modification allowed 10d and 10e to be isolated in 78%
and 85% yield, respectively.
Cp
1
then: Δ
TsN
Ti
4
4 + 5
THF, 0 o
1 h
C
1 h
Cp
temp (oC)
4:5 (NMR)
7: not isolated
23
35
55
1:20
1:1
15:1
D
CHO
Me
DCl, 0 o
C
O2 (1 atm)
D
90%
15–42%
(by NMR)
N
N
Ts
Ts
5-d2
Scheme 1. Reactivity of Titanacyclobutane 7.
8
It was unnecessary to isolate this transient species, which we
observed in 1H NMR spectra of unpurified reaction mixtures
before protonolysis.[25] Instead, the thermal stability of 7 was
established by forming the metallacycle in situ at 0 °C, then
To interrogate the role of temperature on the formation and
equilibration of titanacyclobutanes I and II, we studied the
2
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observed titanacyclobutane stability trends
general reaction scheme
1 (1.2 equiv)
THF, 0 oC or –10 o
Cp
Cp
Cp
Cp
Cp
Cp
Cp
Cp
Me
C
Ti
Ti
≈
Ti
>>
Ti
>
H
–then add–
HCl or TFA or SiO2
H
H
group I
[0 oC]
group II
[0 oC]
group III
[–10 oC, 2 equiv of 1]
group IV
[not observed]
alkene 11
alkane 12
group I. exocyclic alkenesb
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
N
N
N
N
N
N
Boc
Ac
Boc
R
Boc
Boc
12a: 89%
12b: 77%
12c: 31% (33%)c,d
12d (R = Boc): 83%
12e (R = Ts): 92%
12f: 87%
12g: 81%
group II. endocyclic alkenese
group III. acyclic alkenesg
Me
Me
Me
Me
Me
Me
Me
Me
!
!
H
Me
H
H
H
H
BnO
H
β
β
O
O
N
Me
BnO
O
Bn
HO
Me
O
12h: 72% (>95%)c
12i: 60% (>95%)c,f
d.r. ≥ 20:1, !:β = 13:1
12j: 50% (>95%)c,f
d.r. ≥ 20:1, !:β = 17:1
12k: 47% (>95%)c,f
d.r. ≥ 20:1
12l: 61% (80%)c,d
12m: 71% (78%)c,d
group IV.
trisubstituted alkenes
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
Me
N
N
N
N
Bn
Bn
Ts
Ts
R
CF3
11t: n.r.
[limitation]
12n: 61% (77%)c
12o: 44% (55%)c,d
12p: 81% (>95%)c
12q (R = OMe): 38% (44%)c,d 12s: 70% (85%)c,d
12r (R = Br): 61% (67%)c,d
Scheme 3. Scope and Limitations of Titanium-Mediated Alkene Hydromethylation.[a]
[a] Yields are based on isolated 12. [b] Conditions: 1.2 equiv of 1, 1 h; 3 M aq, HCl, 0 °C, 6 h. [c] Conversion of 11 to 12 as judged by 1H NMR spectra of the
unpurified reaction mixture. [d] Unreacted 11 was removed by treating the mixture of 11 and 12 with m-CPBA.[25] [e] Conditions: 1.2 equiv of 1, 3 h; TFA, –78 °C ®
rt, 6 h. [f] SiO2 in EtOAc used in place of TFA. [g] Conditions: 2 equiv of 1, THF (0.1 M), –10 °C, 3 h; TFA, –78 °C ® rt, 6 h.
and 12j. This outcome is consistent with a requirement to place
conversion of methyl eugenol (9e) to products 10e using 1H NMR the titanium atom in the least sterically encumbered position. In
spectroscopy. Thus, 9e was reacted with 1.2 equiv of 1 in THF comparison, branched acyclic alkenes in Group III (11l-s) were
(0.1 M) for 3 h at various temperatures, then treated with TFA at less reactive, requiring an excess of 1 (2 equiv) and longer
–78 °C. These experiments revealed a temperature window of – reaction times (3 h, –10 °C) to obtain useful results. Nevertheless,
1,1-disubstituted alkyl (11l-n) and (hetero)aryl (11o-s) alkenes
were transformed to branched alkanes 12l-s in reasonable yield.
Alkanes 12q-s derived from a-methyl styrenes are noteworthy, as
this alkene class is a limitation of the Baran hydromethylation.[9]
On the other hand, trisubstituted alkenes (e.g. 11t) were
unreactive. In addition, substrates bearing pendent aldehydes,
ketones, or esters were complicated by competitive carbonyl
methylenation.
With these limitations established, we set out to exploit the
noted differences in alkene reactivity to achieve site-specific
hydromethylation (Scheme 4). Thus, we found that the acyclic
alkene in 13 reacted selectively to give 14 exclusively. We also
observed complete selectivity for the a-olefin in 15 to afford 16 in
84% yield. Likewise, the cyclic alkene of 17 was functionalized,
leaving the branched acyclic alkene untouched en route to amide
18. In contrast, the a-olefin of 19 reacted preferentially to give
pyrrole 20 in 72% yield following oxidation of the pyrroline during
10 °C to 10 °C to achieve a high conversion to 10e (≥95%). Using
these conditions, the regioselectivity (b/l ratio) improved from 8:1
at –10 °C to >25:1 at 0 °C. Taken together, these data
demonstrate the importance of time and temperature as variables
for reaction optimization.
With these considerations in mind, the hydromethylation of
substituted alkenes was explored. As highlighted in Scheme 3,
alkenes 11 were divided into four groups (I–IV) based the
structure of the titanacyclobutane formed during the reaction.
Group I included exocyclic 1,1-disubstituted alkenes derived from
nitrogen heterocycles (11a-g). Substrates of this type reacted at
0
°C to afford branched products exclusively. Pendent
carbamates (12a) and amides (12b) were tolerated, as were
small- (12d-f) and medium-sized (12g) ring systems. In contrast,
hydroquinoline 11c reacted slowly under the standard conditions,
presumably because the resultant titanacyclobutane is more
sterically hindered.
Group II consisted of endocyclic 1,2-disubstituted alkenes purification.[31] Taken together, these competition experiments
(11h-k), which reacted at 0 °C in identical fashion to Group I. established the following order of alkene reactivity: a-olefins >
Similarly, heterocyclic carbamates (12h), ethers, and alcohols cyclic alkenes > acyclic branched alkenes >> tri-substituted
(12i-k) were tolerated.[30] We observed that the methyl group was alkenes.
selectively delivered to the more congested position (a) within 12i
3
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COMMUNICATION
[3]
[4]
S. D. Friis, M. J. Johansson, L. Ackermann, Nat. Chem. 2020, 12, 511–
519.
For select reviews, see: a) M. Beller, J. Seayd, A. Tillack, H. Jiao, Angew.
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A. Green, Organic Reactions 2019, 383–470; c) I. P. Beletskaya, C.
Najera, M. Yus, Russ. Chem. Rev. 2020, 89, 250–274.
For Markovnikov hydromethylation methods, see: a) Z. N. Parnes, G. I.
Bolestova, I. S. Akhrem, I. S.; D. N. Kursanov, J. Chem. Soc., Chem.
Commun. 1980, 748; b) J. Terao, T. Watanabe, K. Saito, N. Kambe, N.
Sonoda, Tetrahedron Lett. 1998, 39, 9201–9204; c) F.-G. Fontaine, T. D.
Tilley, Organometallics 2005, 24, 4340–4342.
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Kischkewitz, K. Bergander, A. Studer, Chem. Sci. 2019, 10, 6210–6214;
b) Q. Zhu, D. G. Nocera, J. Am. Chem. Soc. 2020, 142, 17913–17918.
Zirconium-catalyzed carboalumination (ZACA) reactions also provide an
entry point to formal alkene hydromethylation, see: a) E. Negishi, Dalton
Trans. 2004, 827–848; b) D. E. Van Horn, L. F. Valente, M. J. Idacavage,
E. Negishi, J. Organomet. Chem. 1978, 156, C20–C24.
a. trisubstituted vs. branched acyclic
Me
Me
Me
Me
Me
1 (2 equiv)
THF, –10 oC, 3 h
[5]
then: TFA
40% (73% brsm)
single isomer
Me
Me
Me
Me
Me
13
14
[6]
[7]
b. acyclic – branched vs. unbranched (⍺-ofelin)
Me
Me
1 (1.2 equiv)
THF, 0 oC, 6 h
O
O
OMe
OMe
then: TFA
84%
[8]
[9]
For examples in natural product total synthesis, see: a) J. E. McMurry,
M. D. Erion, J. Am. Chem. Soc. 1985, 107, 2712–2720; b) G. Pattenden,
L. Roberts, A. Blake, J. Chem. Soc., Perkin Trans 1 1998, 863–868; c) J.
Deng, Y. Ning, H. Tian, J. Gui, J. Am. Chem. Soc. 2020, 142, 4690–4695.
H. T. Dao, C. Li, Q Michaudel, B. D. Maxwell, P. S. Baran, J. Am. Chem.
Soc. 2015, 137, 8046–8049.
Me
single isomer
(15:1 b/l)
Me
15
16
c. acyclic vs. cyclic
[10] For a related catalytic MHAT hydroalkylation method, see: S. A. Green,
T. R. Huffman, R. O. McCourt, V. van der Puyl, R. A. Shenvi, J. Am.
Chem. Soc. 2019, 141, 7709–7714.
[11] S. H. Pine, Org. React. 1993, 43, 1–90.
[12] A. E. Salvati, J. A. Law, J. Liriano, J. H. Frederich, Chem. Sci. 2018, 9,
5389–5393.
[13] M. Lautens, S. Hiebert, J. Am. Chem. Soc. 2004, 126, 1437–1447.
[14] M. Nakamura, K. Matsuo, T. Inoue, E. Nakamura, Org. Lett. 2003, 5,
1373–1375.
Me
1 (1.2 equiv)
THF, 0 oC, 3 h
Me
Me
N
N
O
then: TFA
68%
single isomer
O
17
18
[15] a) F. Bertozzi, M. Pineschi, F. Macchia, L. A. Arnold, A. J. Minnaard, B.
L. Feringa, Org. Lett. 2002, 4, 2703–2705; b) W. Zhang, L. Wang, W. Shi,
Q. Zhou, J. Org. Chem. 2005, 70, 3734–3736.
[16] J. C. Lorenz, J. Long, Z. Yang, S. Xue, Y. Xie, Y. Shi, J. Org. Chem.
2004, 69, 327–334.
[17] Competitive reduction of nucleophilic radical A was reported as a
problem using sterically hindered substrates. See reference 9.
[18] a) F. N. Tebbe, G. W. Parshall, G. S. Reddy, J. Am. Chem. Soc. 1978,
100, 3611–3613; b) F. N. Tebbe, R. L. Harlow, J. Am. Chem. Soc. 1980,
102, 6149–6151.
d. cyclic vs. ⍺-ofelin
1 (1.2 equiv)
THF, 0 oC, 3 h
Me
N
N
then: TFA, O2
72%
single isomer
(≥25:1 b/l)
Me
O
O
19
20
Scheme 4. Site-specific Hydromethylation.
[19] a) S. H. Pine, R. Zahler, D. A. Evans, R. H. Grubbs, J. Am. Chem. Soc.
1980, 102, 3270–3272; b) K. C. Ott, R. H. Grubbs, J. Am. Chem. Soc.
1981, 103, 5922–5923; c) S. L. Buchwald, R. H. Grubbs, J. Am. Chem.
Soc. 1983, 105, 5490–5491; d) S. C. H. Ho, D. A. Straus, R. H. Grubbs,
J. Am. Chem. Soc. 1984, 106, 1533–1534.
[20] For seminal reports, see: a) T. R. Howard, J. B. Lee, R. H. Grubbs, J.
Am. Chem. Soc. 1980, 102, 6876–6878; b) P. J. Krusic, F. N. Tebbe,
Inorg. Chem. 1982, 21, 2900–2902; c) J. B. Lee, K. C. Ott, R. H. Grubbs,
J. Am. Chem. Soc. 1982, 104, 7491–7496.
[21] For examples, see: K. A. Brown–Wensley, S. L. Buchwlad, L. Cannizzo,
L. Clawson, S. Ho, D. Meinhardt, J. R. Stille, D. Straus, R. H. Grubbs,
Pure Appl. Chem. 1983, 55, 1733–1744 and references therein.
[22] Hydromethylation was noted as a byproduct in carbonyl methylenation
reactions employing excess 1, see: D. C. Harrowven, M. C. Lucas, P. D.
Howes, Tetrahedron 2001, 57, 791–804.
[23] The utility of 1 in carbonyl–olefin metathesis using highly functionalized
substrates has been demonstrated, see: a) J. R. Stille, R. H. Grubbs, J.
Am. Chem. Soc. 1986, 108, 855–856; b) K. C. Nicolaou, M. H. D.
Postema, C. F. Claiborne, J. Am. Chem. Soc. 1996, 118, 1565–1566.
In summary, a method for the direct hydromethylation of
alkenes has been developed. This chemistry harnesses Tebbe’s
reagent (1) to generate titanacyclobutanes from alkenes. These
transient 1,3-dianion equivalents react in situ with exogenous acid
to furnish net hydromethylation products with excellent
regioselectivity. In defining the scope and limitations of this
method, we established a clear hierarchy for alkene reactivity that
allows for site-specific hydromethylation within complex,
polyfunctional molecules. This feature is especially useful for
natural product synthesis and the late-stage diversification of
bioactive small molecules.
Acknowledgements
[24] Deposition
Number
2059774
contains
the
supplementary
crystallographic data for compound 3. These data are provided free of
charge by the joint Cambridge Crystallographic Data Centre:
www.ccdc.cam.ac.uk/structures.
This work was supported by the NIGMS branch of the National
Institutes of Health (NIH) under award number R01GM125926.
We thank Dr. Xinsong Lin (FSU) for assistance with X-ray
crystallography and mass spectrometry. We are also grateful to
Professor Joel Smith (FSU) for valuable discussions.
[25] See the Supporting Information for additional details.
[26] Reagent 1 was prepared from Cp2TiCl2 and AlMe3 (2.0 M in PhMe).
Based upon current prices for these reagents, the cost of 1 was
~$1.1/mmol when prepared as described in the Supporting Information.
In our hands, the titration of 1 with 2-tert-butylcyclohexanone was difficult
to interpret. An alternative titration using p-anisaldehyde was developed.
These procedures were adapted from an earlier report: L. F. Cannizzo,
R. H. Grubbs, R. H. J. Org. Chem. 1985, 50, 2386–2387.
Conflict of Interest
[27] Tebbe studied the degradation of 1 in PhMe. Several titanium species
The authors declare no conflict of interest
are generated, including (Cp2TiCl)2. See reference 20b.
[28] For an overview of methods relating to ketone gem-dialkylation, see: D.
Seebach, Angew. Chem., Int. Ed. 2010, 49, 2–8.
[29] The thermal cycloreversion of titanacyclobutanes to alkenes and
Cp2TiCH2 has been described. See references 19 and 20.
Keywords: titanacyclobutane • hydromethylation • site-specific •
[30] The relative stereochemistry of 12i–12k was assigned by comparison to
previously reported data for these structures.
complex molecule synthesis • organometallics
[31] Structures 17 and 19 were intrinsically sensitive to oxidation and slowly
oxidize to the corresponding acyl pyrroles under ambient conditions.
[1]
[2]
H. Schönherr, T. Cernak, Angew. Chem., Int. Ed. 2013, 12256–12267.
K. Feng, R. E. Quevedo, J. T. Kohrt, M. S. Oderinde, U. Reilly, M. C.
White. Nature 2020, 580, 621–627.
4
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10.1002/anie.202103278
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Me
Et
Et
Me
Me
Cp
Cp
i. THF, 0 o
ii. TFA
C
Cl
It’s all about Me. Reported herein is a method for the direct
N
+
Al
Ti
N
Markovnikov hydromethylation of unactived alkenes. This chemistry
enables site-specific incorporation of a methyl group into complex,
poly-functional molecules.
O
O
Tebbe’s reagent
[~$1.1/mmol]
chemoselective
& site-specific
Cp
Cp
! 30+ examples
Institute and/or researcher Twitter usernames: @FSURsearch
Ti
! scope & limitations
! simple procedure
! rules for selectivity
titanacyclobutane
1,3-dianion
5
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