Synthesis of amino-diamondoid pharmacophores: Via photocatalytic C-H aminoalkylation

Article abstract of DOI:10.1039/d0cc02804e

We report a direct C-H aminoalkylation reaction using two light-activated H-atom transfer catalyst systems that enable the introduction of protected amines to native adamantane scaffolds with C-C bond formation. The scope of adamantane and imine reaction partners is broad and deprotection provides versatile amine and amino acid building blocks. Using readily available chiral imines, the enantioselective synthesis of the saxagliptin core and rimantadine derivatives is also described.

Full text of DOI:10.1039/d0cc02804e

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Synthesis of Amino-Diamondoid Pharmacophores via
Photocatalytic C–H Aminoalkylation
William K. Weigel III,a,b Hoang T. Dang,a,b Hai-Bin Yang,‡a and David B. C. Martin*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
We report a direct C–H aminoalkylation reaction using two light-
activated H-atom transfer catalyst systems that enable the
introduction of protected amines to native adamantane scaffolds
with C–C bond formation. The scope of adamantane and imine
reaction partners is broad and deprotection provides versatile
amine and amino acid building blocks. Using readily available
chiral imines, the enantioselective synthesis of the saxagliptin core
and rimantadine derivatives is also described.
Chiral amines are an important class of molecules found in
bioactive natural products and pharmaceuticals, making them
desirable synthetic targets. Many methods have been
developed for their synthesis from classical approaches (e.g.
Strecker, Ugi reactions1 to modern stereoselective catalytic
strategies.2 Aminoalkylation reactions that simultaneously
introduce a C–C bond and amine are particularly powerful
(Figure 1A). Three main strategies for radical-mediated
aminoalkylation are commonly used:3 addition of an alkyl
radical to an imine derivative (disconnection i),4,5,6 radical
conjugate addition into an ɑ,β-dehydroamino acid (discon-
nection ii),7 or the addition of a captodative ɑ-amino radical to
a radical acceptor.8 The use of imine derivatives as radical
acceptors has grown in recent years and typically involves the
use an alkyl halide in conjunction with a radical initiator.
Improvements on traditional initiators (e.g. Et3B/O2,
Bu3SnH/AIBN, etc.) with their associated drawbacks have been
reported, such as photoredox activation of organosilicon and
organoboron compounds by Molander, Gong and Friestad.9
The importance of chiral amines highlights an ongoing need for
efficient, stereoselective methods for their synthesis.
Figure 1. Bioactive aminoadamantanes and synthetic approaches for the preparation of
aminoalkylated molecules.
high reactivity required to perform H-atom transfer (HAT) of
unactivated C–H bonds often leads to incompatibility with
redox-sensitive functional groups and site selectivity issues on
complex substrates.10 As a result, most examples have focused
on more reactive substrates such as ethers with activated α-
heteroatom-C–H bonds that can be selectively targeted.11 The
C–H functionalization of diamondoids is challenging due to
unusually high bond dissociation energies (BDEs) of these
hydrocarbons (96 and 99 kcal/mol for 2º and 3º C–H bonds,
respectively) and potential regioselectivity issues.12 The amino-
alkyl derivatives typified by rimantadine (2, Figure 1B) are
especially prevalent in a variety of anti-virals,13 HDAC inhibitors
(martinostat)14 and anti-diabetic agents (saxagliptin 3),15a high-
lighting the utility of this pharmacophore.15b A direct amino-
alkylation of diamondoids would provide an ideal method for
their synthesis, which often relies on the reductive amination
of acyl-derivatives such as 4, as shown in Figure 1C.13a The
adamantyl-glycine core of saxagliptin (3) has been synthesized
The direct aminoalkylation of hydrocarbons is an attractive
but challenging method for direct C–H functionalization. The
a. Department of Chemistry, University of California Riverside, Riverside, California
92521, United States.
b. Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, United
States.
† Electronic supplementary information (ESI) available: Experimental procedures,
optimization studies and analytical data of the products. See
DOI: 10.1039/x0xx00000x
‡ Current address: School of Chemical Engineering and Light Industry, Guangdong
University of Technology, Guangzhou 510006, People’s Republic of China.
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using asymmetric reductive amination or Strecker
approaches.15 This strategy necessitates pre-functionalization
of adamantane and complicates the introduction of additional
substituents on the adamantane core. Herein, we describe a
photocatalytic method enabling the direct aminoalkylation of
adamantanes without these drawbacks (Figure 1D).
Table 2. Scope of imine and hydrazone derivatives in aminoalkylation of adamantanes.
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DOI: 10.1039/D0CC02804E
Key to the efficient substitution of adamantanes is an HAT
step that can overcome the strong C–H BDEs while maintaining
high chemo- and regioselectivity. We recently reported a
method for the alkylation of diamondoids with alkenes using a
photoredox/HAT dual catalytic system.16 This alkylation
reaction displays unusual selectivity for the 3º C–H bonds of
adamantanes over weaker C–H bonds. Using the combination
of an oxidizing photocatalyst (Ir(dF(CF3)ppy)2(d(CF3)bpy)PF6, Ir-
1) with an electron-deficient quinuclidine catalyst (quinuclidin-
3-yl benzenesulfonate, Q-1),†16 we explored the reaction of
adamantane with various imine derivatives under blue-light
irradiation (Table 1).17,18 We found that Ts-imines and Boc-
imines were efficient coupling partners, giving the
aminoalkylated products 9 and 10 in 75% and 72% yield,
respectively. Hydrazones were also competent radical
acceptors in this reaction, however with lower efficiency (12
and 14, 22-37% yield). Substitution of the phenyl ring with an
electron-withdrawing substituent such as p-F and p-CN led to
higher yields, as shown for N-Boc 11 (80% yield) and N-Bz-
hydrazide 13 (78% yield), consistent with a LUMO-lowering
effect and the nucleophilic character of the adamantyl
radical.19 A Ns-protected imine was less efficient due to
competing decomposition pathways (see ESI†). Other imines
such as a glyoxalate derivative and a cyclic, trisubstituted
sulfonylimine were excellent partners, giving esters 15 and 16
in 67% and 83% yield, respectively. Sulfonamide product 16
Table 1. Survey of imine and hydrazone derivatives in aminoalkylation of adamantane.
Notes. Reactions performed on a 0.5 mmol scale using 2 x 40W 456nm lamps
over 24-72 h. All yields are isolated yields. aSolvent is CH3CN. b2 equiv H2O added.
has adjacent fully substituted carbons, highlighting the power
of radical addition reactions to generate congested C–C bonds.
We next explored the scope of imine and adamantane
partners. As shown in Table 2, both electron-deficient and
electron-rich Ts-imines are coupled with moderate to high
yield.
A pyridine substituent was tolerated with some
substrate degradation observed (22, 48% yield). Electron-rich
adamantanes were high yielding while electron-withdrawn
adamantanes with a chloro and NHBoc substituent were incor-
porated with lower efficiency. The scope of hydrazide products
Notes. Reactions performed on a 0.5 mmol scale using 2 x 40W 456nm lamps
over 18-48 h. Reaction temp. maintained at approx. 28 °C with a small cooling
fan. See ESI† for structure of Ir-1, Q-1 and details. All yields are isolated yields.
2 | J. Name., 2012, 00, 1-3
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was broad, provided an electron-withdrawing substituent was
present on the aryl group. Both ortho- and para-substitution
was tolerated. The highest yields were achieved with electron-
rich adamantanes and yields were diminished for acetyl- and
hydroxyadamantane substrates (compare 34 and 35, 28 and
36). In general, the reaction rate was slower for hydrazone
substrates. The scope of cyclic, alpha-3º amine products was
also broad. Electron-rich and moderately electron-deficient
adamantanes led to the highest yields for 37–39 (74–80%
yield) while acetyl- and cyano-substituents showed more
significant decreases (66% for 40, 40% for 41).
Table 3. Scope of chiral imines acceptors for preparation of enantioenriched amines.
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DOI: 10.1039/D0CC02804E
We then turned to the synthesis of enantioenriched ɑ-
adamantyl amines using our dual catalytic system in
conjunction with chiral N-sulfinyl imines. The use of N-sulfinyl
imines as chiral auxiliaries is a well-established strategy for the
asymmetric synthesis of ɑ-branched amines and ɑ-amino
acids.20 There are fewer but nonetheless important examples
of stereocontrolled radical additions.4ab,21 Unfortunately, we
found that using our Ir-1/Q-1 system with a N-tolylsulfinimine
43 (R” = p-Tol) resulted in poor conversion and some decom-
position, therefore we looked for possible alternative catalysts.
Kamijo and coworkers have shown that using 5,7,12,14-
pentacenetetraone (PT) as a photocatalyst provides a viable
method for generating the desired 1-adamantyl radical 6.22,6e
Gratifyingly, we found that the use of PT with 390 nm LEDs
gave benzylic N-tolylsulfinamide 45 in good yield with mode-
rate stereoselectivity (9:1 d.r., Table 3). A glyoxalate-derived
imine also proceeded with 9:1 d.r., albeit in lower yield (47,
41% yield). Only marginal asymmetric induction was observed
using the Ellman N-tert-butylsulfinyl auxiliary (48, 1.3:1 d.r.).
The stereocontrol was significantly improved by switching to
N-mesitylsulfinimines, providing 46 and 49 in good yields and
>20:1 d.r.. Notably, use of N-mesitylsulfinimines provides a
direct route to enantiopure adamantyl glycine precursor 49
and the 3-hydroxyadmantyl glycine core of saxagliptin 50 in a
direct and highly selective manner, enabling further
exploration of these unnatural building blocks.15
Next, we explored the performance of the aminoalkylation
method with cyclohexane and tetrahydrofuran (Scheme S2†).
Using the PT system, cyclohexane reacted with an N-tosyl
imine in 31% yield. Tetrahydrofuran was selectively amino-
alkylated at the α-oxy-C–H bond using Ir-1/Q-1 in 50% yield.
While the yields of these reactions are lower than related
transformations by Gong6e and Dilman’s recent report6d with a
decatungstate HAT catalyst, we have found that TBADT is
ineffective for activating adamantanes in this reaction (see
ESI† for details). As a result, the catalyst systems described
here provide a complementary substrate scope. Efforts to ge-
neralize this reaction manifold are ongoing in our laboratory.
Finally, we moved to the deprotection of representative
reaction products to provide the free amines (Scheme 1). The
use of samarium diiodide allowed efficient cleavage of the N–
NHBz bond of 27 to afford free amine 51 (79% yield). Similarly,
deprotection of the tosyl group was very efficient (92% yield).
Cleavage of the sulfinyl group in sulfinamide 49 proceeded
smoothly under acidic conditions to afford the corresponding
adamantylglycine ethyl ester 52 in 53% yield.
Notes. Reactions performed on a 0.3 mmol scale using 2 x 40W 390nm lamps
over 24-48 h. Reaction temperature is approx. 34 °C. All yields are isolated yields.
d.r. values obtained via 1H NMR analysis of crude product mixture (see ESI† for
details). aReaction performed on a 0.5 mmol scale. bSolvent is 1:1 DCE:PhCl.
Based on related mechanistic work, we propose that this
transformation parallels the previously reported alkylation
reaction via either a direct HAT process for PT (Scheme 2) or
an indirect HAT process for Ir-1/Q-1 (Scheme S1†).16,11b For the
direct HAT process, excitation of PT with light generates an
excited state capable of H-atom abstraction to give radical 6.22
Addition of the radical to the imine or hydrazone gives an N-
centered radical 53. Turnover would either proceed via HAT
from semiquinone PT-H to aminyl radical 53 or single electron
reduction by PT-H followed by proton transfer. For the indirect
process, excitation of the photocatalyst Ir-1 followed by
oxidation of quinuclidine Q-1 yields the corresponding radical
cation which can undergo HAT to give the adamantyl radical
6.16,17 Addition of the radical gives aminyl radical 53, which can
be reduced by Ir(II) to the corresponding anion. Proton
transfer from the quinuclidinium ion gives the final product 5
and closes the catalytic cycle. While we cannot rule out an
alternative mechanism proceeding via reduction of the imine
or hydrazone to a radical anion at this time, the similar
efficiency observed for a variety of N-substituents (Tables 1
and 3) with a range of reduction potentials is less consistent
with literature examples that proceed via this mechanism.6e,24
In conclusion, we have described a direct aminoalkylation
reaction promoted by selective hydrogen atom abstraction. A
dual catalytic system consisting of an Ir-photocatalyst and
quinuclidine co-catalyst enables the efficient coupling of
diverse imines, hydrazones and adamantane coupling partners
with high chemoselectivity. In addition, a quinone catalyst PT
provides high yields for the enantioselective synthesis of
aminoalkylated derivatives of known bioactive molecules and
unnatural amino acids. The catalyst systems described tolerate
Scheme 1. Deprotection reactions with SmI2 and TFA to afford free amines.
This journal is © The Royal Society of Chemistry 20xx
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This work was supported by generous start-up funds from
UC Riverside and the University of Iowa. NMR instrumentation
was supported by funding from the NSF (CHE-1626673, UCR)
and the U.S. Army (W911NF-16-1-0523, UCR) and from the NIH
(S10-RR025500, UI). HRMS was supported by funding from the
NSF (CHE-0541848, UCR; CHE-0946779, UI).
Conflicts of interest
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There are no conflicts to declare.
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