Cu-Catalyzed hydrophosphorylative ring opening of propargyl epoxides: Highly selective access to 4-phosphoryl 2,3-allenols

Article abstract of DOI:10.1039/c6cc05428e

A novel CuI-catalyzed cross-coupling of propargyl epoxides with P(O)H compounds is disclosed. The reaction proceeded efficiently under mild conditions to give 4-phosphoryl 2,3-allenols in good to high yields with excellent selectivity. The utility of the products was demonstrated and a plausible mechanism was also proposed.

Full text of DOI:10.1039/c6cc05428e

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DOI: 10.1039/C6CC05428E
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Cu-Catalyzed Hydrophosphorylative Ring Opening of Propargyl
Epoxides: Highly Selective Access to 4-Phosphoryl 2,3-Allenols
Ruwei Shen,*a Jianlin Yang,a Haipeng Zhao,a Yu Feng,a Lixiong Zhang,a Li-Biao Han*b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel CuI-catalyzed cross-couplings of propargyl epoxides with
P(O)H compounds is disclosed. The reaction proceeded efficiently
under mild conditions to give 4-phosphoryl 2,3-allenols in good to
high yields with excellent selectivity. The utility of the products
was demonstrated and a plausible mechanism is also proposed.
2,3-Allenols are highly desired building blocks in advanced
organic synthesis1 as they offer expeditious routes to a wide
range of useful compounds such as conjugated dienes,2 1, 3-
enynes,3 vinyl epoxides,4 dihydrofurans,5 furanones6 and other
heterocycles.7 Among the various synthetic methods, the
transition metal catalyzed ring openings (SN2′-type) of
propargyl epoxides with organometallic reagents such as
Grignard, organolithium, organozinc and organoboron reagents
represent one useful and reliable protocol (Scheme 1i, type a).8-
Scheme 1 TM-catalyzed SN2’-type reaction of propargyl epoxides to produce allenols.
13
Metals including Cu,9 Pd,10 Rh11 and Fe12 have been found
several 4-stannyl 2,3-allenols were obtained.14a Recently the
same group also investigated the Cu/Pd-catalyzed borylation of
propargyl epoxides and related compounds with B2pin2, 14b, 14c
and a selective production of 4-borylated 2,3-allenol is
achieved using CuI-P(1-nap)3 as the catalyst.14b We are
currently engaged in a joint project geared towards efficient
synthesis of useful organophosphorus compounds via new
catalytic transformations of the easily available P(O)H
compounds.16 Recently we have developed an efficient Cu-
catalyzed coupling of propargyl acetates with P(O)H
compounds proceeding via a unique nucleophilic interception
of Cu-allenylidene intermediates by phosphorus nucleophiles to
afford allenylphosphoryl compounds in high yields under mild
conditions.16a In this paper we wish to communicate a new
highly selective and atom-economic ring-opening of propargyl
epoxides by P(O)H compounds catalyzed by a simple copper
salt.17 This reaction ultimately leads to a novel class of useful 4-
phosphoryl 2,3-allenol derivatives in high yields (Scheme 1ii).
We began our study by examining the reaction of 2-ethynyl-
2-phenyloxirane (1a) and dimethyl phosphonate (2a) with the
treatment of a catalytic amount of Cu(1) species (Table 1).
While the possible competition reactions, e.g., the potential
direct attacks of the nucleophile to the epoxide ring, were firstly
concerned, we were pleased to observe that the reaction gave
capable of promoting the transformation with efficient C-C
bond formation and selectively opening the epoxide ring to give
anti- or syn-configured 2,3-allenols with high selectivity.
Furthermore, optically active allenols are also accessible by
11, 12
using chiral propargyl epoxides as substrates10b,
applying a chiral catalyst9e with this strategy.
or
While this methodology has met with considerable success to
offer access to a variety of 2,3-allenols via the formation of C-C
bonds based on the use of carbon-nucleophiles (Scheme 1i,
Type a), very few examples are known on similar catalytic
reactions with heteroatomic counterparts although such a type
of transformations is very promising as synthetic methods to
afford various 4-functionalized 2,3-allenols via the formation of
14, 15
C-heteroatom bonds (Scheme 1i, type b).
A relevant
example, to our knowledge, was first described by Szabó in a
detailed study on the palladium-catalyzed substitutions of
propargyl substrates with dimetallic reagents in 2005, in which
a.State Key Laboratory of Materials-Oriented Chemical Engineering, College of
Chemistry and Chemical Engineering, Nanjing Tech University, Nanjing 210009,
China. E-mail: shenrw@njtech.edu.cn
b.National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba,
Ibaraki, 305-8565, Japan. E-mail: libiao-han@aist.go.jp
Electronic Supplementary Information (ESI) available: Experimental procedures,
characterization data of the products. See DOI: 10.1039/x0xx00000x
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Table 1 Optimization data on reaction conditions a
Chloro, bromo, trifluoromethyl and phenyl substituents are
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DOI: 10.1039/C6CC05428E
tolerated (entries 2-5). The reaction was also successfully
performed with 1g bearing a steric hindering tert-butyl, giving
3f in 95% yield with no variation of reaction efficiency (entry
6). In addition to 2a, diethyl phosphonate 2b also reacted with
1a to give 3g in good yield (entry 7). Probably due to the steric
effect, the reaction of dibutyl phosphonate 2c produced the
coresponding product 3i in a lower yield while the reaction of
diisopropyl phosphonate 2d did not give the desired product
(entries 8 and 9). On the other hand, diphenylphosphine oxide
2e is a suitable substrate for the reaction. As examplified in
entries 10-12, the reactions of 2e with 1a
, 1c or 1g produced the
corresponding products 3j 3l in good to high yields. To obtain
-
some information on the stereochemistry of the reaction,
propargyl epoxide 1h was prepared. It was observed that the
reaction of 1h with 2a produced 3m in 77% yield with a dr
value of 56/44 (entry 13). The reaction of 1h with 2e
demonstrated a slightly good diastereoselectivity, affording 3n
with a dr value of 75/25 (entry 14). The disubstituted propargyl
epoxide 1i also gave a mixture of stereoisomers (entry 15).
Finally, the substrate 1j bearing a free hydroxyl group is also
examined, which afforded the expected product 3p in a modest
yield (entry 16).
Table 2 Cu-catalyzed synthesis of 4-phosphoryl 2,3-allenols a
aConditions: 1 (0.36 mmol), 2 (0.3 mmol), copper salt (5 mol%), Ligand (6 mol%) if
added, iPr2NEt(10 mol%) in a solvent (2 mL), 0 oC,
2
h. bIsolated yields.
e
cUnidentified byproducts were obtained (weight < 10 mg). dNo ligand. No
catalyst. f iPr2NEt was not added.
3a in 79% yield with an excellent regioselectivity in the
presence of 5 mol% of CuI and 6 mol% of TMEDA with 10
i
mol% of Pr2NEt at a first attempt (entry 1). A small amount of
unidentified byproducts were also obtained, yet we reasoned
that these identities should result from the transformations of 1a
only, but not the epoxide-opening of 1a by possible attack of
the nucleophile 2a, as the 31P NMR spectroscopy of the crude
mixture clearly show only one peak at ca. 17.5 ppm assigned to
be 3a. The formation of the possible byproducts 3a’ or 3a” was
totally not observed. Subsequent screening of the ligands shows
that the use of 1,10-Phen or dppe gave improved yields (90-
92%, entries 3 and 4). Surprisingly, a blank experiment reveals
that CuI alone also catalyzed the reaction, and cleanly gave the
product in high yield without loss of the reaction efficiency
(entry 5). Similar unidentified byproducts were undetected by
TLC. The reaction could also be catalyzed by other copper salts.
Thus, CuCl gave 3a in 89% yield, while CuBr and Cu(OAc)2
both gave 3a in 83% yield (entries 6-8). However, no reaction
took place in the absence of a copper salt or the amine base
(entries 9 and 10). Finally it is worth noting that the reaction is
critically dependent on the solvent and MeOH is the best. THF,
DCM and MeCN all gave 3a in low yields (entries 11-13). 3a
was not formed in DMF and only a trace amount was detected
in toluene (entries 14 and 15).
i
aConditions: 1 (0.36 mmol), 2 (0.3 mmol), CuI (5 mol%), Pr2NEt (0.03 mmol) in
With the optimal conditions, the scope of the reaction was
briefly explored. As shown in Table 2, a series of propargyl
epoxides bearing substituted phenyl groups reacted smoothly
with 2a affording the corresponding products in high yields.
MeOH (2 mL). bIsolated Yield. cThe reaction was conducted on 1 mmol scale
based on 2a. dEtOH as a solvent. e6 mol% of dppe was added. Reactions were
f
performed on 0.6 mmol scale based on 2e. g dr: 56/44. hdr: 75/25, determined
from its esterified derivative with HOAc (see ESI). i dr: 55/45.
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At the current stage, internal propargyl epoxides are not well in
applicable in the reaction. However, experimental results on
these substrates are informative for a mechanism consideration alkoxide intermediate
1
may induce the nucleophilic attack of 2' (tautVoimeweArrtifcolerOmnlionef
DOI: 10.1039/C6CC05428E
2
) to the δ-position of the propargyl epoxide to form a Cu-
A
. Protonation of A then gives the
(Scheme 2). As shown in eq. 1, the reaction of 1k with 2a product (path a). Considering the facility of the reactions for
catalyzed by CuI gave 4a only in 12% yield. The major product terminal propargyl epoxides, another mechanism may also
is 1-methoxy-2-phenyldec-3-yn-2-ol (5a), arising from an operate, and probably as a major path (path b). The terminal
epoxide-ring opening reaction by MeOH probably due to the substrate
dual activation of both the epoxide ring and the triple bonds by intermediate
a Cu(I) species. A similar result was also obtained from 1l ligand exchange results in the formation of intermediate
bearing a phenyl group at the terminal of the alkyne. epoxide-ring opening and C-P bond formation sequence then
Interestingly, the yield of 4a could be improved to 79% by takes place to give Cu-allenyl intermediate , protodemetal-
adding dppe as a ligand and with a molar ratio of 2a 1k to 2/1, ation of which gives the product and regenerates the catalyst.
1
first reacts with Cu(I) salt to form a Cu-acetylide
. The coordination of 2' to the Cu center via
. An
B
C
D
/
yet 1l failed to give a better result under identical conditions.
These results suggest that the two competative pathways (SN2'
by P(O)H vs SN2 by MeOH) are very sensitive to the electronic
property of the alkynyl moiety for nonterminal substrates. On
the other hand, the P(O)H partner also appears crucial for a
successful transformation of internal propargyl epoxides into
allenols as the reaction of 2e with 1k did not give the desired
product (eq. 2). In contrast, a control experiment by performing
the reaction of 2a, 2e and 1a with equivalent molar ratio gave
3a and 3j in 30% and 64% yield, indicating that 2e is however
more reactive than 2a in reactions of terminal propargyl
epoxides (eq. 3). These results indicate that different
mechanisms may operate in the SN2' reactions of terminal and
nonterminal substrates. Finally, almost no deuterium
incorporation was observed at the C1 position in the
Scheme 3 A plausible mechanism
Notably, the resulted products are very attractive synthetic
building blocks due to the versatile reactivity of the dense
functionalities. Some representative transformations of 3a are
presented in Scheme 4. Thus, the electrophilic cyclization of 3a
with I2 gave the phosphorus cycle
successfully coupled with 4-biphenylboronic acid upon a Pd
catalyst to afford the phosphoryl 1,3-dienes in 89% yield with
excellent stereoselectivity.20 In addition, 3a also readily reacts
with carboxylic acids to give the esterified products
hydrophosphorylative ring-opening product of 1a-d
(eq. 4).18
The H/D exchange may indicate the involvement of a Cu-
alkynide intermediate in the reaction.19
6 in 61% yield. 3a also
7
8
.
Particularly, the reaction of 3a with 3-phenylpropiolic acid
afforded the ester-tethered alkyne-allene product 8b, a valuable
precursor for complex ring synthesis via cyclization reaction21
as exemplified by compound 9.
Scheme 2 Reactivity of internal vs terminal propargyl epoxides. aConditions: 1i or 1j
(0.36 mmol), 2a (0.3 mmol), CuI (5 mol%), iPr2NEt (0.03 mmol) in MeOH (2 mL).
i
bConditions: 1i or 1j (0.3 mmol), 2a (0.6 mmol), CuI (5 mol%), dppe (6 mol%), Pr2NEt
(0.03 mmol) in MeOH (2 mL).
Scheme 4 Synthetic transformations of 3a (Conditions: (a) I2 (2.0 equiv), CH2Cl2, rt,
A plausible mechanism is proposed in Scheme 3. Dual overnight. (b) 4-biphenylboronic acid (2.0 equiv), 5 mol% PdCl2(Ph3P)2, H2O, reflux, 3 h.
(c) RCO2H (1.1 equiv), DCC (1.1 equiv), DMAP (5 mol%), CH2Cl2, 0 oC. (d) Tol, 110 oC, 48 h)
coordination of Cu(1) complex to both the alkyne and epoxide
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1989, 30, 2387; (b) C. Spino and S. Frechette, Tetrahedron
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View Article Online
Lett., 2000, 41, 8033; (c) C. Deutsch, A. Hoffmann-Roder, A.
DOI: 10.1039/C6CC05428E
Domke and N. Krause, Synlett., 2007,
5, 737; (d) Cu-
In summary, we have disclosed an efficient Cu-catalyzed
atom-economic ring-opening of propargyl epoxides with
P(O)H compounds to afford a new class of 4-phosphoryl
2,3-allenols. The reactions proceed under mild conditions
and give the products highly selectively in good to high
yields. Further investigations into the reaction scope,
stereochemistry and target-oriented synthesis of phosphorus
compounds via the transformations of the densely
functionalized products are underway and will be reported
in due course. Financial support from the National Natural
Science Foundation of China (21302095), Research Fund for
the Doctoral Program of Higher Education of China
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and
Jiangsu
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