Hydroalkylation of Styrenes with Benzylamines by Potassium Hydride

Article abstract of DOI:10.1002/hlca.202100120

A method for the synthesis of 1,3-diarylpropylamines through hydroalkylation of styrenes with benzylamines by potassium hydride has been developed. The protocol is initiated by solvothermal treatment of benzylamines with KH at 100 °C to generate deprotonated anionic species, which undergo selective C-alkylation with arylalkenes at 0 °C to ambient temperature to afford 1,3-diarylpropylamines as the major product.

Full text of DOI:10.1002/hlca.202100120

HELVETICA
chimica acta
Accepted Article
Title: Hydroalkylation of styrenes with benzylamines by potassium
hydride
Authors: Jia Hao Pang, Bin Wang, Kohei Watanabe, Ryo Takita, and
Shunsuke Chiba
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10.1002/hlca.202100120
Helvetica Chimica Acta
HELVETICA
Hydroalkylation of styrenes with benzylamines by potassium hydride
Jia Hao Pang,a Bin Wang,a Kohei Watanabe,b Ryo Takita,*,b and Shunsuke Chiba*,a
a Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371 (Singapore) e-mail: shunsuke@ntu.edu.sg
b Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
e-mail: takita@mol.f.u-tokyo.ac.jp
Dedicated to Professor E. Peter Kündig in celebration of his 75th birthday
A method for the synthesis of 1,3-diarylpropylamines via hydroalkylation of styrenes with benzylamines by potassium hydride has been
developed. The protocol is initiated by solvothermal treatment of benzylamines with KH at 100 °C to generate deprotonated anionic species,
which undergo selective C-alkylation with arylalkenes at 0 °C-ambient temperature to afford 1,3-diarylpropylamines as the major product.
Keywords: Hydroalkylation • benzylamines • arylalkenes • potassium hydride
Generation of benzylic carbanions through deprotonation with strong
Introduction
bases and their ensuing regioselective addition onto styrenes enable
efficient construction of 1,3-diarylpropane motifs.[7] The method was
The 1,3-diarylpropylamine motif is found as a key structural unit in
pioneered by Pines,[8-13] and more recently, Guan and Kobayashi
various biologically active small molecules such as prenyltransferase
inhibitor 1,[1] GPR199 modulator 2,[2] and histone deacetylase inhibitor
advanced the state-of-the-art, where benzylic carbanions derived from
3[3] (Scheme 1A). Commonly, synthesis of 1,3-diarylpropylamines
could be conceived through the reductive amination (Scheme 1B-i)[4,5]
or Mannich/Petasis type disconnection approaches[6] either via a
combination of arylanion nucleophiles and aldimine electrophiles
(Scheme 1B-ii) or that of arylethylanion nucleophiles and aldimine
electrophiles (Scheme 1B-iii). Nonetheless, development of facile
construction methods of the 1,3-diarylpropylamine scaffolds from
readily available feedstocks would be of need to diversify their
chemical synthesis. In this work, we explored a unusual disconnection
approach that leverages -amino benzylic carbanions and styrenes
(Scheme 1B-iv).
alkyl(hetero)arenes (Scheme 2A),[14,15] diarylmethanes (Scheme
2B),[16,17] 1,3-diarylpropenes (Scheme 2C),[18] benzyl sulfides (Scheme
2D)[19] were utilized for the nucleophilic addition to styrenes.
A
O
Ph
Ph
Me
N
N
Ph
HN
Ph
F
N
Me
N
GPR199 modulator (2)
N
O
Me
HO
N
O
N
H
Ph
CN
Ph
prenyltransferase inhibitor (1)
histone deacetylase inhibitor (3)
B
Ar2
+ R-NH2 + H–
(i)
Scheme 2. Addition of benzylic carbanion to styrenes.
Ar1
O
Despite these advances, engagement of benzylamines in their
deprotonative benzylic alkylation with styrenes remains elusive. When
primary and secondary amines are employed, the base-mediated
deprotonation occurs on the amine site and the resulting amide anions
show the propensity to undergo hydroamination.[20-24] Interestingly,
Hultzch observed that the reaction of benzylamine (4) and styrene (5)
catalyzed by KN(SiMe3)2 and TMEDA affords not only hydroamination
Ar2
Ar2
NHR
(iv)
Ar2
+
+
Ar1
Ar1
(iii)
(ii)
NR
Ar1
NR
+
Ar2
Ar1
NHR
Scheme 1. (A) Bioactive molecules having a 1,3-diarylpropylamine moiety. (B)
Retrosynthetic approaches toward 1,3-diarylpropylamines.
1
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10.1002/hlca.202100120
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products 6 and 6’, but also 1,3-diphenylpropylamine (7) as a minor co-
product through hydroalkylation of styrene (5) (Scheme 3). We
hypothesized that there might be an equilibrium between the amide
anion I and benzylic anion II. It should be noted that no formation of 7
was observed when LiN(SiMe3)2 was used, implicating that the counter
alkali metal cation on the bases should impact the reaction course.
Scheme 3. Observation of hydroalkylation of styrene (5) with benzylamine (4).
The research team of the Mitsubishi Gas Chemical Company Inc. also
observed a similar counter cation effect in hydroamination or
hydroalkylation of styrene (5) with 1,3-phenylenedimethaneamine (8)
Scheme 5. Observation of equilibrium between sodium amide and
benzylsodium species.
(Scheme 4).
Namely, use of LiNH2 or NaNH2 facilitates
Based on these backgrounds, we wondered if anionic species
generated by the treatment of benzylamines with alkali metal hydrides
could drive hydroamination or hydroalkylation of styrenes. Herein, we
report selective hydroalkylation of styrenes with benzylamines
mediated by potassium hydride (KH) in THF, enabling facile synthesis
of 1,3-diarylpropylamines.
hydroamination to form 9 as the predominant pathway, whereas a
combination of NaNH2 and KOt-Bu switches the selectivity toward
hydroalkylation to provide 10 as the major product.[25]
Results and Discussion
We began our investigation using benzylamine (4) (2 equiv) and
styrene (5) as the model substrates (Table 1). We observed that the
treatment of a mixture of 4 and 5 with NaH (1.1 equiv) in THF at 80 °C
resulted in formation of the hydroamination product 6 and the
hydroalkylation product 7 in 17% and 19% yields, respectively (entry
1). The use of lithium iodide (LiI) as an additive could not improve the
over all mass-balance of the reaction (entry 2). We reasoned that the
poor mass-balance should stem from anionic polymerization of
styrene (5) and thus we examined use of larger counter alkali metal
cations to prevent the propagation of the anionic polymerization.
Interestingly, the use of cesium iodide (CsI) (entry 3) and cesium
fluoride (CsF) (entry 4) could enhance the mass-balance and
moreover, the reaction with CsF pushed the selectivity towards the
formation of hydroalkylation product 7 (entry 4). We reasoned that the
use of CsF would accelerate the counter ion metathesis between NaH
and CsF due to the higher lattice energy of the resulting NaF (910 kJ
mol-1) than that of NaI (682 kJ mol-1).[28] We observed that increasing
the amount of benzylamine (4) to 2.5 equiv further improved the mass-
balance (entry 5). Curiously, employment of potassium hydride (KH)
(1.1 equiv) instead of NaH drastically accelerated the consumption
rate of styrene (5), completing the reaction within 0.5 h to afford 7 in
60% yield (entry 6). This observation with KH was consistent even if
Scheme 4. Counter cation effect in hydroamination/alkylation of styrene (5)
with 1,3-phenylenedimethaneamine (8).
On the other hand, we recently discovered that sodium amide anions
could be generated by the solvothermal deprotonation of aliphatic
amines with sodium hydride (NaH) in the presence of dissolving iodide
such as sodium iodide (NaI) or lithium iodide (LiI) and the resulting
amide anions could undergo nucleophilic amination of methoxyarenes
in both intra and intermolecular manners.[26,27] During this study, we
also observed the equilibrium between the amide anion and the in the
reaction of substrate 11 (Scheme 5). Namely, the reaction of 11 with
NaH and LiI in THF at 90 °C provided a mixture of tetrahydroquinoline
12,
tetrahydro-1H-benzo[b]azepine
13,
and
alkane
14.
Tetrahydroquinoline 12 was formed from amide anion III via
intramolecular nucleophilic aromatic substitution (SNAr), while
tetrahydro-1H-benzo[b]azepine 13 and alkane 14 might be formed
from benzylic anion IV via aza-[1,2]-Wittig rearrangement followed by
intramolecular SNAr and -elimination of imine, respectively.
2
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10.1002/hlca.202100120
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Table 2. Optimization of reaction conditions–2[a]
the reaction was conducted in the absence of CsF (entry 7). These
observations stimulated us to tune the experimental protocol of the
method using KH.
Table 1. Optimization of reaction conditions–1[a]
Entry
NaH or KH
Additive
(equiv)
Time
(h)
Yield of 6
(%)[b]
Yield of 7
(%)[b]
Entry
NaH
or
Additive
(equiv)
Time
(h)
Yields (%)[b]
1
2
NaH
NaH
NaH
NaH
NaH
KH
none
LiI
3
3
17
11
40
5
19
16
21
59
74
58
57
6
7
15
16
KH
1
2
3
KH
KH
CsF
none
CsF
0.3
0.3
24
12
10
0
45
63
0
5
4
0
5
12
0
3
CsI
3
4
CsF
CsF
CsF
none
3
5[c]
6[c]
7[c]
3
11
0
NaH
[a] The reactions were conducted using 1.25 mmol of benzylamine (4) in the
presence of KH (1.1 equiv) and additive (1.1 equiv) in THF (0.2 M) at 100 °C
(in sealed tube) for 1 h, followed by addition of styrene (2) (0.5 mmol) at 0 °C.
[b] 1H NMR yields based on the internal standard.
0.5
0.5
KH
0
[a] The reactions were conducted using 1 mmol of benzylamine (4) and 0.5
mmol of styrene (5) in the presence of NaH or KH (1.1 equiv) and additive
(1.1 equiv) in THF (0.2 M) at 80 °C (in sealed tube). [b] 1H NMR yields of
isolated inseparable mixtures including 6 and 7 based on the internal
standard. [c] The reactions were conducted using 1.25 mmol (2.5 equiv) of
benzylamine (4).
Having optimized the reaction conditions for selective hydroalkylation
of styrene (5) with benzylamine (4) (Table 2, entry 2), we next turned
our attention to investigate the substrate scope with respect to
styrenes for the synthesis of 1,3-diarylpropylamines (Scheme 6). We
found that treatment of an inseparable mixture of 6 and 7 with di-tert-
butyl dicarbonate (Boc2O) allows for separation and isolation of 1,3-
diarylpropylamine as an N-Boc adduct 17 in 61% yield. We set this as
the standardized protocol to examine the reactivity of other styrenes.
As for the substituents on the aryl group, the method allowed for
installation of methyl groups to afford hydroalkylation products 18-21
in good yields regardless of their positions including sterically hindered
2-methylphenyl and 2,4,6-trimethylphenyl groups (for 20 and 21).
Moreover, introduction of electron-donating methoxy (for 22-24),
phenoxy (for 25), and dimethylamino (for 26) groups did not impact the
productivity for the hydroalkylation process. Of worthy to note is the
rate acceleration of the hydroalkylation step observed in the reaction
with 2-methoxyphenyl substrate (for 24), implicating the presence of
the chelation between the methoxy group and potassium cation in the
carbanion intermediate formed via the addition of the benzylic
carbanion onto the alkene. It should be noted that the reactions with
electron-deficient styrenes having halogen atoms or a trifluoromethyl
group on the aryl group did not afford the desired hydroalkylation
product at all. In these cases, we observed anionic polymerization of
styrenes. Next, we examined the substituent effect on the alkene. The
hydroalkylation of -methylstyrene was found to proceed smoothly to
give 27 in good yield, whereas that of 1,1-diphenylethylene resulted in
the isolation of 28 in 35% yield, along with the formation of
diphenylmethane (28’) and 1,1,3,3-tetraphenylpropane (28”) in 7%
We observed that solvothermal treatment of benzylamine (4) with KH
and CsF at 100 °C could generate a reddish suspension, indicating
the formation of anionic species.[29] Subsequent addition of styrene
(2) at 0 °C allowed for rapid trapping of styrene (5) to form 6 and 7 in
13% and 51% yields, respectively, within 0.3 h (Table 2, entry 1).
Moreover, the pretreatment of 4 with KH in the absence of CsF
followed by addition of styrene (5) resulted in better mass balance,
providing 6 and 7 in 10% and 63% yields, respectively (entry 2). In
these cases, pyrrolidines 15 and 16 could also be identified as minor
co-products. We elucidated the reaction pathway for the formation of
these co-products at the mechanistic discussion in Scheme 8. On the
other hand, this protocol was not applicable for the use of NaH-CsF
system (entry 3).
3
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and 25% yields, respectively (see the Supporting Information for the
7B). We found that the presence of proton(s) on the nitrogen is
proposed mechanism for the formation of 28’ and 28”).
essential for the productive hydroalkylation.
Namely, N-
methylbenzylamine (35) could be engaged in the hydroalkylation of
styrene (5) under NaH-CsF system (Scheme 7D), whereas no
reactivity was shown in the reaction of N,N-dimethylbenzylamine (37)
(Scheme 7E).
Scheme 7. Scope of benzylamines.
To obtain mechanistic insights on the present selective hydroalkylation
process, we conducted several control experiments (Scheme 8). The
optimization of the reaction conditions revealed that excess use (2.5
equiv) of benzylamines is optimal to realize the productive
hydroalkylation. Indeed, treatment of benzylamine (4) with 1.2 equiv
of KH converted benzylamine (4) to N-benzylimine 38 and
dibenzylamine (39) in 43% and 2% yields, respectively. We assumed
that N-benzylimine 38 is formed through condensation of benzylamine
(4) and aldimine 40, which is generated via -hydride elimination of
amide anion I,[30] whereas dibenzylamine (39) is formed by hydride
reduction of imine 38 with KH[31-34] (Scheme 8A). On the other hand,
treatment of benzylamine (4) with 0.44 equiv of KH, which is exactly
the same stoichiometry with the optimized reaction conditions, could
suppress the formation of 38 and 39 to around 13% combined yield.
We also confirmed that the present hydroalkylation is not mediated via
N-benzylimine 38. Namely, the treatment of N-benzylimine 38 with KH
followed by styrene (5) resulted in formation of pyrrolidine 16 in 13%
yield via [3+2]-cycloaddition of a 2-azaallyl anion,[35-37] which is derived
from deprotonation of 38, with styrene (5), followed by N-alkylation of
Scheme 6. Scope of styrenes. [a] Unless otherwise stated, the reactions were
conducted using 1.25 mmol of benzylamine (4) in the presence of KH (1.1 equiv)
in THF (0.2 M) at 100 °C (in sealed tube) for 1 h, followed by addition of styrenes
(0.5 mmol) at
0 °C (the reaction times as well as the ratio of
hydroamination/hydroalkylation products were noted in the parentheses). After
separation by flash column chromatography, the resulting inseparable mixtures
including amines were treated with Boc2O and NaHCO3 to isolate
hydroalkylation products. The isolated yields were stated. [b] The reaction with
styrene was conducted at 30 °C. [c] Diphenylmethane (28’) and (1,1,3,3-
tetraphenylpropane (28”) were isolated in 7% and 25% yields, respectively,
based on 1,1-diphenylethylene used (see the Supporting Information for details).
We then tested other benzylamines as the nucleophile for
hydroalkylation of styrene (5) (Scheme 7). The hydroalkylation with 1-
naphthylmethylamine (29) proceeded smoothly to afford 30 in 60%
yield (Scheme 7A). Branched amines such as -methylbenzylamine
(31) and diphenylmethylamine (33) were found to be compatible for
the hydroalkylation of styrene (5) (Scheme 7B and C). We observed
that the protocol employing NaH and CsF (Table 1, entry 5) could work
more efficiently in the reaction with -methylbenzylamine (Scheme
4
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an anionic pyrrolidine intermediate with another styrene (5), while no
formation of hydroalkylation products such as 41 and 7 was observed.
It should be noted that pyrrolidine 15 observed in the reactions in Table
2 is formed via protonation of the anionic pyrrolidine intermediate.
Scheme 9. Deuterium labelling experiments with 27 and reactivity of 6.
Based on these observations, a proposed mechanism for KH-
mediated hydroalkylation of styrene (5) with benzylamine (4) was
described in Scheme 10. Pretreatment of benzylamine (4) with KH
allows for generation of amide anion I, which should be under an
equilibrium with benzylic carbanion II. Addition of styrene (5) to the
anionic species triggers selective C-alkylation of II to generate another
benzylic carbanion intermediate V over N-alkylation to form 6.
Subsequent H-transfer of V with the intramolecular primary amine
moiety generates amide anion VI, which is finally protonated via
aqueous work-up to furnish the hydroalkylation product 7.
Scheme 8. Reactivity of benzylamine (4) and N-benzylimine 36 in the
presence of KH.
Next, we examined deuterium labelling experiments (Schemes 9A and
B). Treatment of 1-naphthylmethylamine (29) with 0.44 equiv of KH
followed by aqueous workup with D2O gave 29 back with no deuterium
incorporation at the benzylic position (Scheme 9A). On the other hand,
treatment of deuterated 1-naphthylmethylamine (29-d2) with KH (0.44
equiv) followed by workup with H2O resulted in 76% loss of deuterium
from 29-d2, providing a mixture of 29 and 29-d1 (Scheme 9B). These
results indicated that there is an equilibrium between the amide anion
and the benzylic carbanion, while this equilibrium is biased to the
amide anion.
Finally, we confirmed that a pathway from
hydroamination product 6 to hydroalkylation product 7 via base-
mediated aza-[1,2]-Wittig rearrangement[38] is unlikely (Scheme 9C).
Scheme 10. Proposed mechanisms.
To further understand the present reactivity and selectivity for the
hydroalkylation, we carried out the DFT calculations at the M06-2X/6-
311++G*/SMD(THF)//M06-2X/6-31+G* level of theory. Based on the
previous reports which revealed that potassium amides possess
dimeric (or oligomeric) structures in THF solution,[39-41] we adopted a
dimeric structure as a model complex of the potassium amide. In
addition, given that use of more than 2 equivalents of benzylamine (4)
to KH was required to avoid the undesired side reactions (Scheme 8),
we assumed that the coordination of benzylamine (4) should be
involved in the potassium amide.[18,24] We thus located the potassium
5
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10.1002/hlca.202100120
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amide dimer INT1-N having the coordination of benzylamine (4) and
THF (Scheme 11). The possible pathway for the deprotonation of the
benzylic proton of the coordinated proximal benzylamine (4) was first
examined. The reasonable deprotonation pathway was elucidated
with TSN-C with a reasonable activation barrier (∆G‡ +12.7 kcal/mol) to
give carbanion INT1-C, which is more unstable (+8.6 kcal/mol) than
INT1-N, yet kinetically accessible; these species can exist in an
equilibrium under the reaction conditions. We also found that 1,2-H-
shift from the potassium amide species for the formation of carbanion
species necessitates a very high activation energy and thus this
pathway is unlikely (for details, see the Supporting Information). Next,
starting from the amide anion INT1-N and the carbanion INT1-C, the
subsequent hydroamination and hydroalkylation processes with
styrene (5) were examined and the reaction pathways of the lowest
energy barriers were presented in Scheme 11. The hydroamination
(on the left side of Scheme 11) proceeds via the transition state TS1-N
,
which is located at +19.1 kcal/mol. In the case of the hydroalkylation
process (on the right side), the formation of the carbanion species
INT1-C makes the corresponding potassium cation less crowded and
more accessible by styrene (5). The efficient coordination of styrene
(5) promotes the C–C bond formation smoothly with more stable
transition state TS1-C (+14.2 kcal/mol) than TS1-N for the
hydroamination. These results corroborated the reactivity and
selectivity observed in the present KH-mediated hydroalkylation
process.
Scheme 11. DFT calculations on the hydroamination and hydroalkylation reactions of modeled dimeric species with styrene (5). Energy changes and bond lengths
at the M06-2X/6-311++G*/SMD(THF)//M06-2X/6-31+G* level of theory are shown in kcal/mol and Å, respectively.
6
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Conclusions
[9]
J. Shabtai, H. Pines, ‘Potassium-Catalyzed Reactions of α-Methylstyrene
with Alkylbenzenes’, J. Org. Chem. 1961, 26, 4225-4229.
[10] J. Shabtai, E. M. Lewicki, H. Pines, ‘Potassium-Catalyzed Reactions of
β-Alkylstyrenes and Anethol with Alkylbenzenes’, J. Org. Chem. 1962, 27,
2618-2621.
We have presented a new disconnection approach toward 1,3-
diarylpropylamines based on base-mediated hydroalkylation of
styrenes with benzylamines. Use of potassium hydride as the base is
the key enabling the present unusual hydroalkylation selectively over
the common hydroamination.
[11] H. Pines, W. M. Stalick, ‘Synthetic Applications of Homogeneous Base-
Catalyzed Additions of Aromatic Alkylheterocyclics to Conjugated
Hydrocarbons’, Tetrahedron Lett. 1968, 9, 3723-3726.
[12] H. Pines, N. E. Sartoris, ‘Base-Catalyzed Reactions. XXXIV. Alkali Metal
Catalyzed Side-Chain Aralkylation of 2- and 4-Alkylpyridines with Styrene,
α-Methylstyrene, and cis- and trans-β-Methylstyrene’, J. Org. Chem.
1969, 34, 2113-2118.
Supplementary Material
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/MS-number.
[13] H. Pines, ‘Base-Catalyzed Carbon-Carbon Addition of Hydrocarbons and
of Related Compounds’, Acc. Chem. Res. 1974, 7, 155-162.
[14] D.-D. Zhai, X.-Y. Zhang, Y.-F. Liu, L. Zheng, B.-T. Guan, ‘Potassium
Amide-Catalyzed Benzylic C−H Bond Addition of Alkylpyridines to
Styrenes’, Angew. Chem. Int. Ed. 2018, 57, 1650-1653.
Acknowledgements
This work was financially supported by Nanyang Technological
University (NTU) and the Singapore Ministry of Education (Academic
Research Fund Tier 2: MOE2019-T2-1-089) for S.C. as well as JSPS
KAKENHI grant JP19K06992, and the Naito Foundation for R.T.
Computational calculations were performed using the resources of the
Research Center for Computational Science at Okazaki, Japan. We
thank Yoichi Takano, Masahiro Shimizu and Kazuyoshi Uera
(Mitsubishi Gas Chemical Company Inc.) for helpful discussion. We
are grateful to the referees of this manuscript for their valuable
suggestion.
[15] Y. Yamashita, H. Suzuki, I. Sato, T. Hirata, S. Kobayashi, ‘Catalytic
Direct-Type Addition Reactions of Alkylarenes with Imines and Alkenes’,
Angew. Chem. Int. Ed. 2018, 57, 6896-6900.
[16] Y. F. Liu, D. D. Zhai, X. Y. Zhang, B. T. Guan, ‘Potassium-Zincate-
Catalyzed Benzylic C-H Bond Addition of Diarylmethanes to Styrenes’,
Angew. Chem. Int. Ed. 2018, 57, 8245-8249.
[17] A. Kondoh, C. Ma, M. Terada, ‘Synthesis of Diarylalkanes through an
Intramolecular/intermolecular Addition Sequence by Auto-Tandem
Catalysis with Strong Bronsted Base’, Chem. Commun. 2020, 56, 10894-
10897.
[18] X.-Y. Zhang, L. Zheng, B.-T. Guan, ‘Lithium Diisopropylamide Catalyzed
Allylic C–H Bond Alkylation with Styrenes’, Org. Lett. 2018, 20, 7177-
7181.
Author Contribution Statement
S.C. designed the studies. J.H.P. and B.W. performed the
experiments. K.W. and R.T. conducted DFT calculations. J.H.P., R.T.
and S.C. wrote the manuscript.
[19] Y.-F. Liu, L. Zheng, D.-D. Zhai, X.-Y. Zhang, B.-T. Guan, ‘Dimeric
Potassium Amide-Catalyzed α-Alkylation of Benzyl Sulfides and 1,3-
Dithianes’, Org. Lett. 2019, 21, 5351-5356.
[20] S. M. Coman, V. I. Parvulescu, ‘Nonprecious Metals Catalyzing
Hydroamiation and C-N Coupling Reactions’, Org. Process Res. Dev.
2015, 19, 1327-1355.
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