Reductive cleavage of aryl O-carbamates to phenols by the Schwartz reagent. Expedient link to the directed ortho metalation strategy?

Article abstract of DOI:10.1021/ol401547d

A general, mild, and efficient method for the reductive cleavage of aryl O-carbamates to phenols, 1 → 2 using the Schwartz reagent is reported. The method is selective, tolerating a large number of functional groups; may be carried out by direct or by an economical in situ procedure; and, notably, establishes a synthetic connection to the directed ortho metalation strategy (Figure 1) allowing new entries into difficult to prepare contiguously substituted aromatics and heteroaromatics.

Full text of DOI:10.1021/ol401547d

ORGANIC
LETTERS
2013
Vol. 15, No. 16
4102–4105
Reductive Cleavage of Aryl O-Carbamates
to Phenols by the Schwartz Reagent.
Expedient Link to the Directed Ortho
Metalation Strategy‡
Justin Morin, Yigang Zhao, and Victor Snieckus*
Department of Chemistry, Queen’s University, Kingston, Ontario K7L 3N6, Canada
snieckus@chem.queensu.ca
Received June 15, 2013
ABSTRACT
A general, mild, and efficient method for the reductive cleavage of aryl O-carbamates to phenols, 1 f 2 using the Schwartz reagent is reported. The
method is selective, tolerating a large number of functional groups; may be carried out by direct or by an economical in situ procedure; and,
notably, establishes a synthetic connection to the directed ortho metalation strategy (Figure 1) allowing new entries into difficult to prepare
contiguously substituted aromatics and heteroaromatics.
Recently, we developed1 the use of an in situ Schwartz
reagent for the general and efficient conversion of aryl
amides to benzaldehydes which, especially in conjunction
with the appreciated directed ortho metalation (DoM)
chemistry of benzamides,2 provides a new and general
synthetic strategy for the construction and manipulation
of polysubstituted aromatic and heteroaromatic alde-
hydes. In the quest for further applications, we turned to
the aryl O-carbamates (ArOCONR2), the most powerful
directed metalation group (DMG),2 whose recalcitrance to
mild hydrolytic or reductive cleavage2b,d,3 to phenols has
denied its broader use. Based on the structural similarity to
amides and the IR and NMR evidence of Zr-coordination
to a variety of unsaturated groups,4 we rationalized that
the tertiary O-carbamate may be susceptible to reduction
by the Schwartz reagent. Herein we report on the ArO-
CONR2 to ArOH conversion, 1 f 2 (Scheme 1, D), which
occurs under mild conditions and is as highly selective as
for the corresponding amide,1 tolerating a host of standard
functional groups. Significantly, we show that, linked with
the DoM strategy, the Schwartz reduction method fur-
nishes difficult to prepare, contiguously substituted phe-
nols of anticipated value in organic synthesis.
Scheme 1. Methods for Cleavage of Aryl O-Carbamates to
Phenols
‡ Dedicated to Prof. Carmen Najera on the occasion of her 60th birthday.
(1) Zhao, Y.; Snieckus, V. Submitted.
(2) (a) Snieckus, V.; Macklin, T. In Handbook of CÀH Transforma-
tions; Dyker, G., Ed.; Wiley: Weinheim, 2005; Vol. 1, p 106. (b) Clayden, J.
In Chemistry of Organolithium Compounds; Rappoport, Z., Marek, I., Eds.;
Wiley: Chichester, 2004; Vol. 1, p 495. (c) Hartung, C. G.; Snieckus, V. In
Modern Arene Chemistry; Astruc, D., Ed.; Wiley: Weinheim, 2002; p 330.
(d) Snieckus, V. Chem. Rev. 1990, 90, 879.
(3) (a) Schoen, U.; Messinger, J.; Solodenko, W.; Kirschning, A.
Synthesis 2012, 44, 3822. (b) Yamazaki, K.; Kawamorita, S.; Ohmiya,
H.; Sawamura, M. Org. Lett. 2010, 12, 3978. (c) Hao, X.-Y.; Zhou,
Z.-M.; Xue, W.-Z.; Yin, J.; Xu, B.-C. Youji Huaxue 2008,28, 1756. (d) Sanz,
R.; Castroviejo, M. P.; Fernandez, Y.; Fananas, F. J. J. Org. Chem. 2005,
70, 6548. (e) Sibi, M. P.; Snieckus, V. J. Org. Chem. 1983, 48, 1935.
In initial studies,5 we used the Georg amide reduction
procedure6 for the Schwartz reagent mediated aryl
O-carbamate to phenol conversion.
(4) Wailes, P. C.; Weigold, H.; Bell, A. P. J. Organomet. Chem. 1971,
27, 373.
r
10.1021/ol401547d
Published on Web 08/06/2013
2013 American Chemical Society

In the first trial study, N,N-diethyl naphthalene 2-O-
carbamate (chosenbecause ofnonvolatility ofthe expected
product) with freshly prepared5,7 Schwartz reagent (3 equiv)
in THF at rt for 3 h led to complete conversion of starting
material and afforded 2-naphthol in 97% yield (Table 1,
entry 11). Application of these conditions to a variety of
aryl O-carbamates derived from commercially available
phenols afforded the corresponding phenols in moderate
to excellent yields. Selected were a variety of ortho-, meta-,
and para-substituted derivatives with both electron-donating
groups (EDGs) and electron-withdrawing groups (EWGs).
Tolerance of ortho-substituted derivatives was observed
(entry 9). In the meta-series, useful results were achieved
for the nitro (entry 2) and the dimethyl (entry 8) O-carba-
mates and, more significantly, for the trifluoromethyl, fluoro,
and chloro systems (entries 1, 5, and 6) all of which are
potential candidates for synergistic in-between DoM2a,d
creating opportunities for synthesis of difficult to prepare
1,2,3-substituted phenols. In the para-series, aside from the
para-OMe system (entry 3), equally significant synthetic
opportunity is presented by the para-OTf and para-bromo
derivatives (entries 4 and 7) on which Suzuki and related
cross-coupling may be achieved before or after the Schwartz
reagent cleavage of the O-carbamates and thereby lead to
substituted hydroxy biaryls. Potential DoM links are also
available for the naphthalene 2-O-carbamate (entry 11), the
bis-O-carbamate (entry 12) which, unsurprisingly, required
6 equiv of Schwartz reagent, and the pyridine 3-O-carba-
mate (entry 13) all of which afforded phenolic products in
very good yields. For further scope extension, the reduction
of an oxazolidine O-carbamate was also achieved in high
yield (entry 10).
Table 2. Schwartz Reagent Mediated Reduction of DoM-
Derived Aryl O-Carbamates Using the Georg Procedure
Table 1. Schwartz Reagent Mediated Reduction of Aryl
O-Carbamates Using the Georg Procedure
a Yields of isolated products. b Due to the high volatility of 2-chlor-
ophenol, it was benzylated for ease of isolation.
Although, as noted in the discussion for Table 1, a
number of O-carbamates may be derived by or are suitable
for DoM and cross-coupling related chemistry, direct
demonstration of such a synthetic link was sought and
established (Table 2). Thus, Schwartz reduction of two
DoM-derived ortho-substituted phenyl O-carbamates
(entries 1 and 2) proceeds very well and biaryl O-carbamates
(entries 3 and 4), derived by DoMÀSuzukiÀMiyaura cross-
coupling regimens,8 undergo Schwartz reagent cleavage
to phenols in high yields. 3-TMS and 3-halo substituted
naphthalene 2-O-carbamates likewise are smoothly con-
verted to the corresponding phenols (entries 7 and 8). The
newly developed regioselective DoM preparation of
a Yields of isolated products. b 5 equiv of Schwartz reagent required
for full conversion. c 6 equiv of Schwartz reagent required.
(8) (a) See Supporting Information. (b) Anctil, E. J. G.; Snieckus, V.
In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere, A.,
Diederich, F., Eds.; Wiley: Weinheim, 2004; Vol. 2, p 761. (c) Anctil,
E. J. G.; Snieckus, V. J. Organomet. Chem. 2002, 653, 150.
(5) Morin, J. M.Sc. Thesis, Queen’s University, Kingston, ON,
Canada, 2007.
(6) (a) Spletstoser, J. T.; White, J. M.; Tunoori, A. R.; Georg, G. I.
J. Am. Chem. Soc. 2007, 129, 3408. (b) White, J. M.; Tunoori, A. R.;
Georg, G. I. J. Am. Chem. Soc. 2000, 122, 11995.
(7) Buchwald, S. L.; LaMaire, S. J.; Nielsen, R. B.; Watson, B. T.;
King, S. M. Org. Synth. 1993, 71, 77.
(9) (a) Groom, K.; Nilewski, C.; Morin, J.; Snieckus, V. In prepara-
tion. (b) 3-Br-2-naphthalene O-carbamate is also available by ipso-
bromodesilylation of the corresponding TMS derivative; see ref 5.
(10) Electrophilic bromination affords either 1-bromo or 1,6-dibro-
mo 2-naphthols; see: Koelsch, C. F. Org. Synth. 1955, 20, 18.
Org. Lett., Vol. 15, No. 16, 2013
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Table 3. Reductive Cleavage of Aryl O-Carbamates to Phenols
via the in situ Schwartz Method
Table 4. Reductive Cleavage of Heterocyclic N-Amides Using
the Schwartz Reagent
a Yields of isolated products. b Yields in parentheses refer to direct
Schwartz reduction; see Table 1.
these derivatives5,9 allows access to simple 3-substituted-2-
naphthols which are expensive and/or not easily available.10
The Schwartz reagent cleavage of the indole 4-boropinaco-
lato 5-O-carbamate to the corresponding phenol (entry 11),
albeit in low conversion, demonstrates the potential stability
of boronates to the reduction conditions. The sensitivity to
steric effects is demonstrated by the failure to effect reduc-
tion of the 2,6-disubstituted phenyl O-carbamates (entries 5
and 6) and the naphthyl O-carbamates (entries 9 and 10).
Our recent discovery of the economically and practically
advantageous in situ Schwartz conditions for the amide to
aldehyde transformation1 logically led to its application to
the ArOCONR2 f ArOH transformation. Table 3 estab-
lishes that the in situ method is very effective for this reduc-
tion, being complete in several hours (TLC analysis) to give
good yields of isolated phenol products.11 Thus, overall, in
comparison with the direct Schwartz reagent reduction, the
in situ method is a practical, equally efficient, and much less
expensive process for the reductive cleavage of aromatic
O-carbamates to phenols12 which, by these preliminary
studies, appears to tolerate all functional groups previously
established for the Georg amide reduction method.6
a Yields of isolated products. b Boc protection to facilitate product
isolation. c 3 equiv required for complete conversion. d 4db can be
converted into 4da; see ref 13.
Figure 1. Synthetic potential of combined O-carbamate DoMÀ
Schwartz reduction chemistry.
may be fully converted into 4da under acidic conditions
(entry 4).13 Since N-CONEt2 indole is an excellent DMG
for the synthesis of 2- and/or 7-substituted indoles,14 this
method may be used to advantage on indole derivatives for
DMG removal after DoM reactions.
In conclusion, a general, mild, and efficient method for
the reductive cleavageofaryl and heteroarylO-carbamates
to the corresponding phenols using the Schwartz reagent
has been demonstrated.15 As for the benzamide to benzal-
dehyde conversion,1 both direct (Georg) and the new,
As a further brief extension, reductive cleavage of
heterocyclic N-amides by the Schwartz reagent was tested.
Thus, treatment of the indole- and benzimidazole-N-
amides 3aÀ3c with the Schwartz reagent (2 equiv) led
successfully to carbamoyl reductive cleavage in good yields
(Table 4, entries 1À3). In the indazole case, 3d, a 56% yield
of the expected product 4da was obtained accompanied by
the over-reduction side product 4db (43% yield) which
(11) In terms of visual observation, unlike in situ amide reduction
(no precipitate formed), the O-carbamate reduction showed the appear-
ance of precipitation which is assumed to be the Schwartz reagent that
slowly is solubilized by the reaction forming the tetrahedral intermediate as
surmised by Georg in the amide reduction mechanism postulate; see ref 6a.
(12) Zhao, Y. Ph.D. Thesis, Queen’s Univesity, Kingston, ON,
Canada, 2010.
(13) Atkinson, F. L.; Barker, M. D.; Campos, S. A.; Harrison, L. A.;
Parr, N. J.; Patel, V. K. Patent Application: WO 2007028445, 2007.
(14) Hartung, C. G.; Fecher, A.; Chapell, B.; Snieckus, V. Org. Lett.
2003, 5, 1899.
(15) As already partially implied in ref 1, the OSO2NEt2 and OP(O)-
(NEt2)2 groups are inert to reduction; see also ref 12.
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Org. Lett., Vol. 15, No. 16, 2013

more economical, in situ O-carbamate reduction methods
constitute useful procedures for the synthesis of a range of
phenols which are expensive, are unavailable, or require
elaborate preparative methods. Thus, the following useful
synthetic opportunities may be anticipated: combined
DoMÀSchwartz reduction and DoMÀSuzuki cross-cou-
plingÀSchwartz reduction protocols for the construction
of difficult to access contiguous 1,2- and 1,2,3-substituted
and other multisubstituted phenols (Figure 1, A and B).
Finally, in view of the establishment of a selective amide to
aldehyde over O-carbamate to phenol reduction priority
and the highest ranking of the OCONEt2 DMG, manip-
ulation of such systems (Figure 1, A when R = CONEt2)
by DoM chemistry prior to Schwartz reduction offers
additional wide-ranging synthetic value.16
Acknowledgment. We are grateful to NSERC Canada
(Discovery Grant) for continuing support of our synthetic
programs and thank Dr. Toni Rantanen (Snieckus Inno-
vations/Queen’s University) for his crucial polishing of the
manuscript.
Supporting Information Available. Experimental pro-
cedures and analytical data for new compounds and
products. This material is available free of charge via
the Internet at http://pubs.acs.org.
(16) For detailed results of both Schwartz reduction procedures, see
ref 12, ref 5, and full paper in preparation.
The authors declare no competing financial interest.
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