Direct Phosphonylation of N-Carbamate-tetrahydroisoquinoline by Convergent Paired Electrolysis

Article abstract of DOI:10.1055/s-0039-1690899

Mild experimental conditions for a direct phosphonylation of an easily cleavable N-carbamate-tetrahydroisoquinoline have been described under constant current electrolysis. The developed electrochemical process allowed to prepare α-aminophosphonates in moderate to good yields. On the basis of the experimental results, a mechanism proceeding through a convergent paired electrochemical process was enabled to be postulated.

Full text of DOI:10.1055/s-0039-1690899

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–F
letter
A
en
A. Ollivier et al.
Letter
Synlett
Direct Phosphonylation of N-Carbamate-tetrahydroisoquinoline
by Convergent Paired Electrolysis
Anthony Ollivier
Stéphane Sengmany*
Marine Rey
NBoc
NBoc
C
C
NBoc
OR
NH·HCl
O P OR
HCl
+
O
+
O
P
MeCN/THF (3:1)
O
P
Thierry Martens*
Eric Léonel
CCE
P
OR
H
OR
OR
OR
convergent paired
electrolysis
OR
(R = Me, Et, iPr, nBu, Bn, Ph)
OR
Electrosynthèse, Catalyse et Chimie Organique, Université Paris
Est Créteil, CNRS, ICMPE, 2 Rue Henri Dunant, 94320 Thiais,
France
sengmany@icmpe.cnrs.fr
martens@icmpe.cnrs.fr
Received: 26.02.2020
Accepted after revision: 27.03.2020
Published online: 17.04.2020
Previous works:
O
OR'
1)
N
O
Cl
OR'
DOI: 10.1055/s-0039-1690899; Art ID: st-2020-r0109-l
(a) approach 1:
N
O
2) P(OR)3
RO
P
OR
Abstract Mild experimental conditions for a direct phosphonylation of
an easily cleavable N-carbamate-tetrahydroisoquinoline have been de-
scribed under constant current electrolysis. The developed electro-
chemical process allowed to prepare -aminophosphonates in moder-
ate to good yields. On the basis of the experimental results, a
mechanism proceeding through a convergent paired electrochemical
process was enabled to be postulated.
ArCHO
+
P(OR)3
or
AgOAc (cat.)
MS 4 Å, 90–120 °C
N
Ar
(b) approach 2:
(c) approach 3:
NH
RO
N
P O
OR
HP(O)(OR)2
catalyst, O2 or air
HP(O)(OR)2
Ar
Key words electrosynthesis, convergent paired electrolysis, phospho-
nylation, aminophosphonates, N-Boc-tetrahydroisoquinoline
N
H
RO
P O
Ar
O
OR
Present work:
The renewed interest in organic electrosynthesis in re-
cent years is due, among others, to the easier access to car-
bon–carbon or carbon–heteroatom bonds.1 The ability to
generate selectively reduced or oxidized intermediates in
situ, with a simplified and eco-compatible methodology,
replacing conventional reducing and oxidizing agents, con-
tributes to making the approach more attractive. The for-
mation of C(sp3)–P bonds has been the subject of the devel-
opment of chemical or electrochemical methods for the
synthesis of tetrahydroisoquinoline (THIQ) phosphonates
by C1-phosphonylation. -Aminophosphonic acids,2 con-
sidered as bioisosteres of -amino acids, have received spe-
cial attention from the community in medicinal chemistry.3
As our laboratory has an expertise in organic electrosynthe-
sis,4 it is envisaged to take the advantage of this know-how
to develop a direct C(sp3)–P bond formation on this amino
substrate model, while focusing on the mechanistical study
of the coupling. Among different documented chemical ap-
proaches to phosphonylate THIQ at the C1 position, three
main approaches have been envisaged for the synthesis of
tetrahydroisoquinoline phosphonates (Scheme 1).
NBoc
O
NH·HCl
RO P O
P(OR)2
C
C ,
HCl
NBoc
RO
P
MeCN/THF (3:1), rt, 30 mA
undivided cell
OR
OR
Scheme 1 Described chemical approaches for the synthesis of tetra-
hydroisoquinoline phosphonates
In the first approach, isoquinoline or 3,4-dihydroiso-
quinoline is activated by alkyl chloroformate on its iminium
salt form prior to react with trialkyl phosphite under heat-
ing (Scheme 1, a).5 It can be noted that a further step is
mandatory to reduce the double bond when isoquinoline
was employed. Moreover, through this approach, Mukher-
jee and co-workers reported an elegant catalytic enantio-
selective dearomatized phosphonylation of N-acyl isoquino-
linium.6 In the second approach, N-benzyl-tetrahydroiso-
quinoline phosphonates were prepared by
a silver-
catalyzed three-component strategy starting from NH-free
tetrahydroisoquinoline, benzaldehyde derivative, and tri-
alkyl or dialkyl phosphite under heating (Scheme 1, b). Silver
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
A. Ollivier et al.
Letter
Synlett
acetate is used to isomerize exocyclic iminium intermediate
to the thermodynamically stable endocyclic isomer leading
regioselectively to C1-phosphonylation of THIQ.7
Table 1 Experimental Parameters Optimization of THIQ-N-Boc for Di-
rect Electrooxidative Phosphonylation with Dimethyl Phosphitea
O
, electrolyte (0.05 M)
C
The last approach, extensively reported compared to the
two previous ones, constitutes the described traditional
method for the synthesis of tetrahydroisoquinoline phos-
phonates from N-aryl tetrahydroisoquinoline using aerobic
conditions in the presence of catalytic8 or stoichiometric
oxidant,9 or by photoredox catalysis10 to achieve C(sp3)–H
and P–H cross-dehydrogenative couplings via iminium in-
termediate formation (Scheme 1, c). However, the prepara-
tion of tetrahydroisoquinoline phosphonates by an electro-
chemical method is poorly explored to date11 until recently,
where Xiang and co-workers12 have reported constant cur-
rent electrochemical N-aryl-tetrahydroisoquinoline cou-
plings with dialkyl phosphites. It is important to emphasize
that the employed N-aryl protecting groups are hardly or
not cleavable and the postulated mechanism is only based
on literature reports. At the same time, Ding and co-work-
ers13 have described a less common protocol in organic
electrosynthesis by employing controlled potential (with a
potential difference of 6.6 V between the two electrodes) in
the presence of additive base to phosphonylate successfully
unprotected tetrahydroisoquinoline derivatives. In this
present work, a simple electrochemical approach of C(sp3)–
P bond formation under constant current electrolysis and
using an easily cleavable tetrahydroisoquinoline nitrogen
protecting group was disclosed. Additionally, mechanistic
aspects of such electrochemical process were investigated
and proposed, supported by complementary experiments.
C
+
H
P
OMe
OMe
2a (1.2 equiv)
NBoc
OMe
NBoc
1 (0.20 mmol)
solvent, T, I
O
P
OMe
3a
Entry Electrolyte Solvent
Charge I (mA) Temp Yield (%)b
(F/mol)
(°C)
1
2
Et4NBF4
Et4NBF4
Et4NBF4
Et4NBF4
Et4NBF4
Et4NBF4
KBF4
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
2.0
2.0
2.4
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.5
3.0
10
15
10
10
10
10
10
10
10
10
10
10
10
10
20
20
20
20
20
20
20
20
45
0
64
53
3
52
4
50c
63d
64e
61
5
6
7
8
LiClO4
45
9
Et4NBF4
Et4NBF4
Et4NBF4
Et4NBF4
Et4NBF4
Et4NBF4
32
10
11
12
13
14
50
MeCN/THF (3:1)
MeCN/THF (1:3)
MeCN/THF (3:1)
MeCN/THF (3:1)
20
20
20
20
68
32
74
80 (70)f
a Reaction conditions: undivided cell, graphite electrodes plates, solvent (2
mL), electrolyte (0.10 mmol), THIQ-N-Boc (0.20 mmol), dimethyl phosphite
(0.24 mmol, 1.2 equiv), constant current, room temperature.
b Yields determined by 1H NMR analysis.
c 1 (0.10 mmol).
Initially,
N-Boc-protected
tetrahydroisoquinoline
d 1 (0.40 mmol).
e 2a (0.48 mmol, 2.4 equiv).
(THIQ-N-Boc) 1 was prepared in quantitative yield by treat-
ing the commercially available tetrahydroisoquinoline with
di-tert-butyl dicarbonate in the presence of catalytic
amount of 4-dimethylaminopyridine in dichloromethane.
Some experimental parameters were then examined to op-
timize the electrooxidative phosphonylation of THIQ-N-Boc
with dimethyl phosphite (2a) as model phosphorous re-
agent (Table 1).
Current intensity was first analyzed. It can be observed
that 10 mA (J = 2.18 mA/cm2) gave the best result in cross-
coupled product when 2.0 F/mol had been passed (Table 1,
entry 1). At higher current intensity (entry 2), the yield de-
creases slightly at the expense of N-Boc-deprotected cross-
coupled product. By increasing the amount of charges to 2.4
F/mol (entry 3), the yield drops to 52% and degradation of
the expected product was observed. In order to limit its
degradation, some experimental parameters were exam-
ined. When lowering substrates concentration by 2 (entry
4), the yield drops to 50%. Conversely, the yield is not affect-
ed by doubling their concentration (entry 5). The increase
of the amount of dimethyl phosphite to 2.4 equivalents has
no effect on the yield (entry 6). The replacement of tetra-
ethylammonium tetrafluoroborate by some other common
electrolytes (entries 7 and 8) resulted in lower yields. Heat-
f Isolated yield.
ing the reaction at 45 °C (entry 9) or lowering the tempera-
ture to 0 °C (entry 10) did not return a better yield. In the
last series of experiments, the solvent was assessed. The ad-
dition of THF as co-solvent to acetonitrile in 1:3 ratio al-
lowed to improve slightly the yield (entry 11). It is import-
ant to note that under these new conditions, no degrada-
tion of the product was observed. Indeed, it is noteworthy
that when the reaction was carried out in acetonitrile with-
out THF, more important amount of the N-Boc-deprotected
product was observed which led to its degradation as this
product is more easily oxidizable than the starting THIQ-N-
Boc substrate. However, the use of an excess of THF versus
acetonitrile has the inverse effect on the yield (entry 12). Fi-
nally, the yield was enhanced by increasing the amount of
charge to 3 F/mol (entry 14) and 70% of phosphonylated
compound was isolated. It noteworthy that, under these op-
timized experimental conditions, direct electrochemical
phosphonylation of unprotected tetrahydroisoquinoline
with dialkyl phosphite leads mainly to a mixture of side
products, only traces of the expected product were ob-
served.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

C
A. Ollivier et al.
Letter
Synlett
With the optimized conditions in hands,14 the scope of
phosphite reagents was explored (Table 2).15
V/SCE). Moreover, it can be noted that the THIQ-N-Boc peak
current intensity (Ip) is comparable with the two-electrons
exchange (iminium formation) compared to that of a solu-
tion of ferrocene.
Table 2 Scope of Phosphites Reagentsa
O
C
C, Et4NBF4 (0.05 M)
NBoc
OR
+
P
H
OR
NBoc
MeCN/THF (3:1), 20 °C
30 mA, 3 F/mol
O
P
OR
OR
1
2a–f (1.2 equiv)
3a–f
Entry
1
R
Product
Isolated yield (%)
70
NBoc
Me
Et
3a
3b
O
O
O
P
OMe
OMe
NBoc
2
3
4
5
6
65
50
71
45
–
P
OEt
OEt
Figure 1 Cyclic voltammetries of substrates: (a) blank, (b) dimethyl
phosphite, (c) diphenyl phosphite, (d) THIQ-N-Boc.
NBoc
i-Pr
n-Bu
Bn
3c
3d
3e
3f
P
OiPr
The deprotection of the coupled product 3a was per-
formed successfully at room temperature in a saturated hy-
drochloric chloride diethyl ether solution to afford the free
amino-tetrahydroisoquinoline chlorhydrate salt in an excel-
lent yield (Scheme 2).
OiPr
NBoc
O
O
O
P
OnBu
OnBu
HCl (g)
NBoc
NBoc
OMe
NH·HCl
O P OMe
Et2O, 20 °C, 3 h
96%
P
OBn
O
P
OBn
OMe
3a
OMe
3a'
NBoc
Scheme 2 Deprotection of THIQ-N-Boc in saturated HCl–diethyl ether
solution
Ph
P
OPh
OPh
a Typical procedure: In a 15 mL electrochemical cell fitted with two graph-
ite plate electrodes were successively added MeCN/THF (3:1, 10 mL, v/v),
tetraethylammonium tetrafluoroborate (0.50 mmol), then THIQ-N-Boc (1
mmol) and dialkyl phosphite (1.20 mmol). The resulting solution was elec-
trolyzed under stirring at 20 °C for 161 min (3.0 F/mol) at constant current
of 30 mA (current density: 3.42 mA/cm2).
Our electrochemical process was then compared to indi-
rect phosphonylation via Shono methoxylation sequence.
For this purpose, THIQ-N-Boc was methoxylated using the
Shono standard procedure in methanol under constant cur-
rent electrolysis. The iminium intermediate is generated
from methoxylated THIQ-N-Boc using boron trifluoride
etherate, followed by trapping with dimethyl phosphite an-
ion, prior deprotonated with sodium hydride, to afford the
expected product in 66% yield. It is important to note that
only traces of the expected product were observed either
with trimethyl phosphite or with dimethyl phosphite non-
deprotonated with a base (Scheme 3). This constitutes an
important result for the mechanistic insight. Finally, this
approach allowed to afford the product in 40% overall yield
in three steps starting from THIQ-N-Boc, which is less effi-
cient compared to our present electrochemical process.
In the case of diphenyl phosphite where our method
failed due to the oxidability of the reagent under our condi-
tions, the coupling was successfully performed via Shono
Good yields were obtained with linear dialkyl phos-
phites (Table 2, entries 1, 2, and 4). When diisopropyl phos-
phite was used, the yield drops to 50% probably due to ste-
ric effect (entry 3). Phosphonylation can be applied with
dibenzyl phosphite although moderate yield was obtained
(2, entry 5). However, phosphonylation failed with diphenyl
phosphite (entry 6). This result can be attributed to the oxi-
dability of diphenyl phosphite (Ep = 1.55 V/SCE, Figure 1, c)
unlike to other phosphites which are not oxidizable under
the electrochemical couplings conditions (Figure 1, b). In-
deed, diphenyl phosphite is more easily oxidizable than
THIQ-N-Boc (Ep = 1.97 V/SCE, Figure 1, d) thus preventing
the coupling to occur, contrary to what has been observed
by Xiang et al.12 with N-arylated THIQ substrates (Ep < 1.55
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

D
A. Ollivier et al.
Letter
Synlett
1) BF3·OEt2, CH2Cl2, –20 °C
2) P(OMe)3 or HP(O)(OMe)2
–20 °C to rt
C
C, Et4NBF4
NBoc
NBoc
OMe
NBoc
MeOH, 20 °C, 30 mA
2 F/mol
60%
OMe
O P
1
OMe
1) BF3·OEt2, CH2Cl2, –20 °C
3a
2) HP(O)(OMe)2, NaH
–20 °C to rt, 66%
Scheme 3 Indirect phosphonylation of THIQ-N-Boc by Shono methoxylation sequence, followed by Lewis acid iminium generation and phosphite trapping
1) BF3·OEt2
CH2Cl2, –20 °C
C
C , Et4NBF4
NBoc
OMe
NBoc
OPh
NBoc
2) HP(O)(OPh)2
Et3N, –20 °C to rt
MeOH, 20 °C, 30 mA
O
P
1
OPh
3f
43% (overall yield)
Scheme 4 Indirect phosphonylation of THIQ-N-Boc with diphenyl phosphite by Shono methoxylation sequence
methoxylation sequence in 43% overall yield (Scheme 4). A
weaker base (triethylamine) was employed since the pKa
value of diphenyl phosphite was estimated to 9.0 unlike di-
methyl phosphite, estimated to 18.4.16 The weak reactivity
of phosphite reagent was observed in the absence of tri-
ethylamine.
In summary, a direct electrochemical phosphonylation
of easily cleavable N-carbamate-tetrahydroisoquinoline un-
der constant current electrolysis was developed. Various
phosphites were successfully coupled in moderate to good
yields. The developed electrochemical process has shown a
better efficiency compared to the three-step Shono ap-
proach. These studies allowed to postulate a mechanism in-
volving a convergent paired electrochemical process where
phosphite anion, formed at the cathode, reacts with imini-
um from THIQ-N-Boc generated at the anode to afford the
coupling product.
Based on the experimental results, the postulated
mechanism for direct phosphonylation of N-carbamate-tet-
rahydroisoquinoline would proceed according to a conver-
gent paired electrolysis (Scheme 5). The two-electron oxi-
dation of THIQ-N-Boc substrate at the anode would lead to
iminium intermediate with proton release, which can be re-
duced at the cathode into dihydrogen in a one-electron pro-
cess. At the same time, the reactive phosphite anion is gen-
erated either by the one-electron direct reduction of dialkyl
phosphite or via the deprotonation by the electrogenerated
base from acetonitrile at the cathode. This key reactive
phosphite anion is supported by chemical experiments (see
Scheme 3). Both iminium and phosphite anion intermedi-
ates would then react in solution to afford the expected
product.
Funding Information
The authors are grateful to the Centre National de la Recherche Scien-
tifique (CNRS) and the Université Paris-Est Créteil for financial sup-
port. A.O. acknowledges the Institut Universitaire de Technologie
Créteil-Vitry for a temporary assistant professor position.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690899.
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NBoc
OR
OR
References and Notes
NBoc
NBoc
O
P
(1) For selected reviews, see: (a) Yan, M.; Kawamata, Y.; Baran, P. S.
Chem. Rev. 2017, 117, 13230. (b) Waldvogel, S. R.; Lips, S.; Selt,
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+
H+
O
P
OR
O
H+
+ 1 e–
1–2H2
1–2H2
+
OR
H
P
OR
OR
+ 1 e–
(2) (a) Mucha, A.; Kafarski, P.; Berlicki, Ł. J. Med. Chem. 2011, 54,
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cathode
Scheme 5 Postulated mechanism for the direct electrooxidative phos-
phonylation of THIQ-N-Boc via a convergent paired electrolysis
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

E
A. Ollivier et al.
Letter
Synlett
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(s, 9 H). 13C NMR (100 MHz, CDCl3):  (mixture of rotamers) =
154.5 (d, J = 3.4 Hz), 153.9 (d, J = 1.1 Hz), 135.0 (d, J = 4.1 Hz),
135.0 (d, J = 4.0 Hz), 130.8 (s), 129.4 (s), 128.9 (d, J = 1.9 Hz),
128.8 (s), 128.0 (d, J = 3.8 Hz), 127.7 (d, J = 3.6 Hz), 127.5 (d, J =
3.1 Hz), 127.3 (d, J = 3.1 Hz), 126.1 (d, J = 2.8 Hz), 126.1 (d, J = 2.8
Hz), 80.8 (s), 80.5 (s), 53.6 (d, J = 7.2 Hz), 53.4 (d, J = 6.7 Hz), 53.3
(d, J = 6.2 Hz), 53.2 (d, J = 149.7 Hz), 53.0 (d, J = 7.4 Hz), 51.8 (d,
J = 152.3 Hz), 40.0 (s), 38.2 (s), 28.7 (s), 28.3 (s), 28.2 (s), 27.9 (s).
31P NMR (162 MHz, CDCl3):  (mixture of rotamers) = 24.44,
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+
H]+:
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342.1465; found: 342.1467.
tert-Butyl 1-(Diethoxyphosphoryl)-3,4-dihydroisoquinoline-
2(1H)-carboxylate (3b)
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Colorless oil, yield 65% (240 mg). FC: ethyl acetate/petroleum
ether (60:40). H NMR (400 MHz, CDCl3):  (mixture of rotam-
1
ers in 55:45 ratio) = 7.47–7.43 (m, 1 H), 7.22–7.11 (m, 3 H), 5.70
(d, J = 20.7 Hz, 0.55 H), 5.51 (d, J = 20.7 Hz, 0.45 H), 4.32–4.27
(m, 0.45 H), 4.15–3.93 (m, 4.4 H), 3.82–3.68 (m, 1 H), 3.55–3.48
(m, 0.45 H), 2.95–2.79 (m, 2 H), 1.49 and 4.48 (2 s, 9 H), 1.40–
1.27 (m, 3 H), 1.19 (t, J = 7.1 Hz, 1.7 H), 1.12 (t, J = 7.0 Hz, 1.3 H).
13C NMR (100 MHz, CDCl3):  (mixture of rotamers) = 154.5 (d,
J = 4.0 Hz), 154.1 (d, J = 1.9 Hz), 135.2 (d, J = 5.6 Hz), 135.1 (d, J =
6.0 Hz), 129.8 (s), 129.4 (d, J = 1.1 Hz), 129.2 (s), 128.9 (d, J = 2.3
Hz), 128.2 (d, J = 3.9 Hz), 127.9 (d, J = 3.3 Hz), 127.4 (d, J = 3.3
Hz), 127.3 (d, J = 3.0 Hz), 126.0 (d, J = 2.7 Hz), 126.0 (d, J = 3.2
Hz), 80.7 (s), 80.30 (s), 63.2 (d, J = 7.3 Hz), 63.0 (d, J = 7.1 Hz),
62.6 (d, J = 7.0 Hz), 62.4 (d, J = 7.6 Hz), 53.6 (d, J = 153.0 Hz), 52.1
(d, J = 152.9 Hz), 40.0 (s), 38.2 (s), 28.4 (s), 28.2 (s), 27.9 (s), 16.4
(s). 31P NMR (162 MHz, CDCl3):  (mixture of rotamers) = 21.92,
21.87. HRMS (ESI+): m/z calcd for C18H29NO5P [M
+
H]+:
370.1778; found: 370.1780.
tert-Butyl 1-(Diisopropoxyphosphoryl)-3,4-dihydroisoquin-
oline-2(1H)-carboxylate (3c)
Colorless oil, yield 50% (198 mg). FC: ethyl acetate/petroleum
1
ether (30:70). H NMR (400 MHz, CDCl3):  (mixture of rotam-
(13) Huang, M.; Dai, J.; Cheng, X.; Ding, M. Org. Lett. 2019, 21, 7759.
(14) Experimental Procedure for Phosphonylation of N-Carba-
mate-tetrahydroisoquinoline
ers in 55:45 ratio) = 7.49–7.40 (m, 1 H), 7.18–7.05 (m, 3 H), 5.64
(d, J = 21.7 Hz, 0.54 H), 5.45 (d, J = 21.1 Hz, 0.46 H), 4.70–4.59
(m, 1 H), 4.58–4.50 (m, 0.53 H), 4.45–4.35 (m, 0.47 H), 4.27 (dd,
J = 13.4, 5.8 Hz, 0.45 H), 4.05–3.97 (m, 0.55 H), 3.73–3.64 (m,
0.53 H), 3.45 (ddd, J = 13.3, 11.6, 4.5 Hz, 0.47 H), 2.98–2.71 (m, 2
H), 1.45 and 1.44 (2 s, 9 H), 1.31–1.25 (m, 5 H), 1.25–1.20 (m, 4
H), 0.99 (d, J = 6.2 Hz, 1.6 H), 0.81 (d, J = 6.2 Hz, 1.4 H). 13C NMR
(100 MHz, CDCl3):  (mixture of rotamers) = 154.5 (d, J = 4.6
Hz), 154.1 (d, J = 1.8 Hz), 135.2 (d, J = 5.6 Hz), 135.1 (d, J = 5.7
Hz), 130.3 (s), 129.7 (s), 129.3 (s), 128.9 (s), 128.4 (d, J = 3.5 Hz),
128.0 (d, J = 3.3 Hz), 127.3 (d, J = 2.9 Hz), 127.1 (d, J = 2.9 Hz),
126.2 (s), 125.8 (d, J = 2.9 Hz), 80.5 (s), 80.1 (s), 72.0 (d, J = 7.4
Hz), 71.7 (d, J = 7.6 Hz), 71.1 (d, J = 7.5 Hz), 70.8 (d, J = 8.0 Hz),
54.1 (d, J = 151.2 Hz), 52.9 (d, J = 155.7 Hz), 39.9 (s), 38.0 (s),
28.4 (s), 28.19 (s), 27.9 (s), 24.41 (s), 24.2 (d, J = 3.0 Hz), 24.1 (s),
24.0 (d, J = 3.4 Hz), 23.8 (d, J = 5.7 Hz), 23.3 (d, J = 5.4 Hz), 23.1
(d, J = 5.2 Hz). 31P NMR (162 MHz, CDCl3):  (mixture of rotam-
ers) = 20.31, 20.17. HRMS (ESI+): m/z calcd for C20H33NO5P [M +
H]+: 398.2091; found: 398.2092.
In an electrochemical cell fitted with two graphite plate elec-
trodes (thickness: 2 mm, submerged area: 8.78 cm2, distance
between the electrodes: 3–5 mm) was added a solution of tetra-
ethylammonium tetrafluoroborate (109 mg, 0.50 mmol, 0.5
equiv) in MeCN/THF (3:1, 10 mL, v/v). The solution was bubbled
with argon for 5 min before the successive addition of N-Boc-
tetrahydroisoquinoline (233 mg, 1.00 mmol, 1.0 equiv) and
dialkyl phosphite (1.20 mmol, 1.2 equiv). After 161 min (3.0
F/mol) of electrolysis (30 mA of current giving rise to a density
of 3.42 mA cm–2) under stirring at 20 °C, the reaction mixture
was quenched with a 1 M HCl aqueous solution (20 mL) and
diluted with Et2O (20 mL). After layers separation, the aqueous
layer was extracted by Et2O (2 × 20 mL). The combined organic
layers were dried over sodium sulfate, filtered and concentrated
in vacuo. The resulting crude product was purified by flash
chromatography on silica gel column to afford the pure phos-
phonylated compound.
tert-Butyl 1-(Dibutoxyphosphoryl)-3,4-dihydroisoquinoline-
2(1H)-carboxylate (3d)
(15) Characterization Data of Compounds 3a–f
tert-Butyl 1-(Dimethoxyphosphoryl)-3,4-dihydroisoquino-
line-2(1H)-carboxylate (3a)
Colorless oil, yield 71% (302 mg). FC: ethyl acetate/petroleum
ether (20:80). H NMR (400 MHz, CDCl3):  (mixture of rotam-
1
Colorless oil, yield 70% (237 mg). FC: ethyl acetate/petroleum
ether (60:40). H NMR (400 MHz, CDCl3):  (mixture of rotam-
ers in 55:45 ratio) = 7.45–7.41 (m, 1 H), 7.24–7.08 (m, 3 H), 5.71
(d, J = 20.5 Hz, 0.55 H), 5.52 (d, J = 20.6 Hz, 0.45 H), 4.28 (m, 0.45
H), 4.00 (m, 0.55 H), 3.83–3.37 (m, 7 H), 2.92–8.81 (m, 2 H), 1.48
ers in 55:45 ratio) = 7.49–7.38 (m, 1 H), 7.21–7.10 (m, 3 H), 5.70
(d, J = 20.8 Hz, 0.55 H), 5.51 (d, J = 20.8 Hz, 0.45 H), 4.30 (dd, J =
13.5, 5.2 Hz, 0.46 H), 4.06–3.97 (m, 3 H), 3.93 (dd, J = 10.0, 6.8
Hz, 0.4 H), 3.88–3.81 (m, 0.6 H), 3.75–3.62 (m, 1 H), 3.48 (ddd,
J = 13.3, 11.4, 4.4 Hz, 0.54 H), 3.00–2.75 (m, 2 H), 1.66–1.57 (m,
1
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

F
A. Ollivier et al.
Letter
Synlett
2 H), 1.48 and 1.47 (2 s, 9 H), 1.43–1.33 (m, 3 H), 1.28–1.21 (m,
2 H), 0.95–0.86 (m, 4 H), 0.86–0.79 (m, 3 H). 13C NMR (100 MHz,
CDCl3):  (mixture of rotamers) = 154.5 (d, J = 4.4 Hz), 154.1 (d,
J = 2.9 Hz), 135.1 (d, J = 5.6 Hz), 129.9 (s), 129.4 (s), 129.4 (s),
128.9 (s), 128.2 (d, J = 3.8 Hz), 127.9 (s), 127.4 (s), 127.3 (s),
127.2 (s), 126.0 (s), 126.0 (s), 80.7 (s), 80.3 (s), 66.9 (d, J = 8.0
Hz), 66.6 (d, J = 7.2 Hz), 66.2 (d, J = 7.0 Hz), 66.1 (d, J = 7.5 Hz),
53.7 (d, J = 151.8 Hz), 52.2 (d, J = 154.4 Hz), 40.9 (s), 40.1 (s),
38.2 (s), 32.5 (d, J = 5.7 Hz), 28.4 (s), 28.2 (s), 27.9 (s), 23.9 (s),
18.7 (s), 18.6 (s), 13.6 (s). 31P NMR (162 MHz, CDCl3):  (mixture
80.9 (s), 80.5 (s), 68.5 (d, J = 7.2 Hz), 68.2 (d, J = 7.1 Hz), 67.9 (d,
J = 6.5 Hz), 67.8 (d, J = 7.5 Hz), 53.8 (d, J = 149.2 Hz), 52.4 (d, J =
152.3 Hz), 40.1 (s), 38.3 (s), 28.4 (s), 28.3 (s), 28.2 (s), 27.9 (s).
31P NMR (162 MHz, CDCl3):  (mixture of rotamers) = 22.74,
22.64. HRMS (ESI+): m/z calcd for C28H33NO5P [M
+
H]+:
494.2091; found: 494.2091.
tert-Butyl 1-(Diphenoxyphosphoryl)-3,4-dihydroisoquino-
line-2(1H)-carboxylate (3f)
Off-white solid, yield 43% (200 mg); mp 81–83 °C. FC: ethyl ace-
tate/petroleum ether (10:90). 1H NMR (400 MHz, CDCl3): 
(mixture of rotamers in 50:50 ratio) = 7.58 (dd, J = 18.2, 6.7 Hz,
1 H), 7.38–7.08 (m, 11 H), 7.04 (d, J = 7.8 Hz, 1 H), 6.75 (d, J = 7.8
Hz, 0.5 H), 6.19 (d, J = 21.0 Hz, 0.5 H), 5.97 (d, J = 19.6 Hz, 0.5 H),
4.50–4.34 (m, 0.5 H), 4.22–4.00 (m, 0.5 H), 3.92–3.78 (m, 0.5 H),
3.74–3.60 (m, 0.5 H), 3.12–2.86 (m, 2 H), 1.49 and 1.48 (2 s, 6
H). 13C NMR (100 MHz, CDCl3):  (mixture of rotamers) = 154.7
(d, J = 4.0 Hz), 154.1 (s), 150.9 (s), 150.8 (s), 150.4 (s), 150.3 (s),
150.2 (d, J = 2.7 Hz), 150.1 (s), 135.5 (d, J = 2.4 Hz), 135.5 (d, J =
2.8 Hz), 129.8 (s), 129.7 (s), 129.6 (s), 129.5 (s), 129.2 (d, J = 2.0
Hz), 128.9 (s), 128.4 (d, J = 4.3 Hz), 128.2 (s), 128.1 (s), 128.0 (d,
J = 3.5 Hz), 127.9 (d, J = 3.4 Hz), 126.4 (s), 125.3 (s), 125.1 (d, J =
4.6 Hz), 124.9 (s), 120.8 (d, J = 4.2 Hz), 120.7 (d, J = 4.3 Hz), 120.4
(s), 120.3 (s), 120.2 (s), 81.3 (s), 80.8 (s), 54.4 (d, J = 150.8 Hz),
53.3 (d, J = 156.8 Hz), 40.4 (s), 38.6 (s), 28.4 (s), 28.3 (s), 28.2 (s),
28.0 (s). 31P NMR (162 MHz, CDCl3):  (mixture of rotamers) =
14.35, 13.88. HRMS (ESI+): m/z calcd for C26H29NO5P [M + H]+:
466.1778; found: 466.1776.
of rotamers) = 21.94, 21.86. HRMS (ESI+): m/z calcd for C22H37
-
NO5P [M + H]+: 426.2404; found: 426.2406.
tert-Butyl
1-[Bis(benzyloxy)phosphoryl]-3,4-dihydroiso-
quinoline-2(1H)-carboxylate (3e)
Off-white solid, yield 45% (220 mg). FC: ethyl acetate/petroleum
ether (20:80); mp 87–89 °C. 1H NMR (400 MHz, CDCl3):  (mix-
ture of rotamers in 55:45 ratio) = 7.52–7.37 (m, 1 H), 7.39–7.01
(m, 13 H), 5.86 (d, J = 20.5 Hz, 0.55 H), 5.62 (d, J = 20.8 Hz, 0.45
H), 5.09–4.94 (m, 2.45 H), 4.94–4.80 (m, 1 H), 4.64 (dd, J = 20.4,
11.8 Hz, 0.55 H), 4.32–4.22 (m, 0.45 H), 4.03–3.93 (m, 0.55 H),
3.74– 3.62 (m, 0.55 H), 3.56–3.43 (m, 0.45 H), 2.95–2.72 (m, 2
H), 1.43 (s, 4.9 H), 1.37 (s, 4.1 H). 13C NMR (100 MHz, CDCl3): 
(mixture of rotamers) = 154.6 (d, J = 3.4 Hz), 154.0 (d, J = 2.0
Hz), 136.3 (d, J = 6.2 Hz), 136.1 (d, J = 5.8 Hz), 135.3 (d, J = 6.6
Hz), 135.2 (d, J = 6.3 Hz), 129.5 (d, J = 1.8 Hz), 129.4 (s), 129.1 (d,
J = 1.7 Hz), 128.9 (s), 128.6 (s), 128.5 (s), 128.4 (s), 128.3 (s),
128.2 (s), 128.1 (s), 128.1 (s), 127.9 (s), 127.8 (s), 127.7 (s), 127.6
(d, J = 3.7 Hz), 127.5 (d, J = 3.3 Hz), 126.2 (s), 126.1 (d, J = 2.8 Hz),
(16) Li, J.-N.; Liu, L.; Fu, Y.; Guo, Q.-X. Tetrahedron 2006, 62, 4453.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F